Substituted Ureas and Methods of Making and Using Same

ABSTRACT

The invention relates to substituted ureas, and compositions comprising the same, which in certain embodiments are useful for treating and/or preventing pain in a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 16/329,984, filed Mar. 1, 2019, now allowed, which is a 35 U.S.C. §371 national phase application of, and claims priority to, InternationalApplication No. PCT/US2017/049726, filed Aug. 31, 2017, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Patent ApplicationNo. 62/382,530, filed Sep. 1, 2016, all of which applications areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Pain is defined as an unpleasant sensory and emotional experience. Pain,however, can be informative and useful. For example, nociceptive pain isoften indicative of injury (e.g., tissue damage), and such paintypically evokes escape or protective behaviors in animals, includinghumans. However, inflammation, cellular and neuronal damage and otherprocesses resulting from injury or disease can lead to states of chronicpathological pain. Hyperalgesia is a condition in which enhancedsensitivity to noxious stimuli is present, and thus the perception ofpain is exaggerated. Allodynia is a condition in which normallynon-noxious stimuli become painful. Persistent or chronic pain,manifested as hyperalgesia and/or allodynia, remains challenging totreat. Many patients do not respond to existing therapeutics, or havetheir pain poorly managed (i.e., inadequate relief), or experiencerelief of an inadequate duration.

Chronic pain contributes to over $600 billion worth of healthcareexpenditures annually, more than the yearly cost of cancer, heartdisease, and diabetes combined. Neuropathic pain affects between 6 and10% of the population, and is associated with decreased quality of lifeand socioeconomic burdens exceeding all other chronic pain disorders. Arecent meta-analysis of more than 200 neuropathic pain clinical trialsindicates that the number of drugs needed to achieve even 50% painrelief in this population is between 4 and 10. This lack of efficacy hasa profound influence on patient quality of life and is a source offrustration for caregivers. Many existing neuropathic pain therapeuticseither have unknown mechanisms or are thought to reduce pain by reducingneuronal excitability.

Administration of opioids to treat pain is a well-recognized andcommonly employed therapy in medicine. Mu opioids from natural sourceshave used by humans for millennia for a wide variety of purposes,including the relief of dysentery and pain. Opium alkaloids were notisolated until the 1800s, and synthetic opioids, whether recapitulationsof nature or newly designed molecules, came much later. Mu opioidagonists are considered gold standard analgesic agents, and are widelyused for the treatment of a variety of mostly moderate-to-severe painconditions in humans.

However, tachyphylaxis, tolerance to opioids and opioid-inducedhyperalgesia can often result during the course of therapy. In suchpatients, increasingly higher doses of opioids are needed to provide anacceptable level of pain relief and, in doing so, the patient is therebysubjected to a higher risk of adverse side effects and safety concerns,which include respiratory depression, constipation, nausea and vomiting.Prolonged opioid therapy to treat chronic pain states may subject thepatient to develop dependence on opioids, suffer opioid withdrawal ondiscontinuation of treatment, and some patients may be more susceptibleto engage in abuse of these medications. These phenomena presentsignificant clinical challenges for pain treatment.

G-Protein coupled receptors are membrane-bound proteins that containseven transmembrane domains, an extracellular N-terminus, intracellularloops and an intracellular C-terminus. The GPCR family constitutes thelargest class of cell surface receptors in the human genome (˜800different members), and small molecules that modulate GPCRs account fornearly one third of all marketed drugs.

Historically, from a conceptual perspective, GPCRs were thought tobehave as switches (off/on), whereupon agonist binding induces a singleconformational change to recruit G-protein coupling, thereby producingsecond-messengers such as cAMP to alter cellular functions (e.g.,polarization (neurons), contractility (myocytes), transcription,translation, and so forth). Antagonists block agonist access, therebyproviding a means to prevent GPCR activation, which is also usefultherapeutically depending upon the specific GPCR.

Upon ligand binding, GPCRs can not only interact with G-proteins asdescribed above, but may also recruit cytosolic proteins of the arrestinfamily. Arrestin recruitment often occurs as a result of phosphorylationby a family of G-protein receptor kinases (GRKs). One role of theβ-arrestin pathway, in contrast to G-protein binding, is to turn offsignaling, possibly serving as an evolutionary ‘brake’ to avoiddeleterious effects of constitutive signaling. β-Arrestins accomplishsignal termination in several ways: 1) G-protein uncoupling causesdesensitization (loss of signaling); 2) degradation of the secondmessenger(s) turns down/off signaling; and 3) receptor internalizationprecludes agonist binding and signaling since the receptor is notexposed/present on the cell membrane. Furthermore, there arenon-classical signaling modalities (e.g., MAP kinase) that can beactivated by β-arrestins.

There is a thus a need in the art for novel compounds and/orcompositions that can be used to treat pain and/or reduce hyperalgesiaand allodynia. In certain embodiments, the compounds and/or compositionsdo not induce significant (or any at all) respiratory depression,constipation, and/or tolerance. The present invention addresses thisunmet need.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates in one aspect to compounds, and compositionscomprising such compounds, that can be used to treat and/or prevent painin a subject in need thereof. In certain embodiments, the subject is amammal. In other embodiments, the mammal is a dog or cat. In yet otherembodiments, the mammal is human.

The invention includes a compound of formula (I), or a salt, solvate,enantiomer, diastereoisomer and/or tautomer thereof:

wherein: A is selected from the group consisting of

B¹ is selected from the group consisting of

and B² is H; or B¹ and B² are independently selected from the groupconsisting of —CH₃ and —CH₂CH₃, or B¹ and B² combine to form a divalentsubstituent selected from the group consisting of —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, and —CH₂CH₂OCH₂CH₂—; R¹ and R² are independentlyselected from the group consisting of H, CH₃, and CH₃ substituted withat least one selected from the group consisting of fluoro, chloro,cyano, hydroxyl and nitro; R³ is selected from the group consisting of Hand CH₃; X is selected from the group consisting of S, O, and N—R^(3′),wherein R^(3′) is selected from the group consisting of hydrogen, alkyland substituted alkyl; each occurrence of R is independently selectedfrom the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro,hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, and substituted phenyl; eachoccurrence of m is independently selected from the group consisting of0, 1, 2 and 3; n is selected from the group consisting of 1, 2 and 3;and each occurrence of p is independently selected from the groupconsisting of 0, 1, 2 and 3.

In certain embodiments, the compounds of the invention bind to the muopioid receptor (MOR). In certain embodiments, the compounds of theinvention activate and/or act as agonists of the mu opioid receptor. Incertain embodiments, upon binding to the MOR, the compounds of theinvention induce certain secondary messenger signaling manifested asintracellular responses, such as but not limited to G-protein signalingand β-arrestin recruitment. In certain embodiments, upon binding to theMOR, the compounds of the invention decrease cyclic adenosinemonophosphate (cAMP) levels. In certain embodiments, upon binding to theMOR, the compounds of the invention activate or behave as agonists ofthe MOR, induce intracellular responses such as but not limited toG-protein signaling and produce a decrease in cAMP.

In certain embodiments, the compounds of the invention do notsignificantly induce secondary messenger signaling, such as, but notlimited to, recruitment, binding to, and/or association withβ-arrestins. More specifically, compounds of this invention havehalf-maximal effective concentration (EC₅₀) values for β-arrestin thatare higher than approximately 1 micromolar (EC₅₀>1 μM) and/or exhibitp-arrestin activity of less than, or equal to 20% of the maximalresponse produced by the synthetic opioid peptide known as DAMGO(H-Tyr-D-Ala-Gly-NMe-Phe-Gly-OH) as defined by the assays describedherein. In certain embodiments, the compounds of the invention induceintracellular responses such as G-protein recruitment and binding, suchas for the proteins known as Gi, decrease cAMP levels, and do notsignificantly induce recruitment, binding to, and/or association withβ-arrestins.

In certain embodiments, the compounds of the invention induceintracellular responses such as G-protein recruitment and binding suchas for the proteins known as Gi, produce an decrease in cAMP, and do notsignificantly induce recruitment, binding to, and/or association withβ-arrestins. In yet other embodiments, the compounds of the inventionare G-protein biased agonists.

In certain embodiments, the compounds of the invention provide relieffrom, and/or alleviate, pain in a subject. In other embodiments, thecompounds of the invention bind to the MOR in a biased manner,decreasing cAMP levels with minimal or no recruitment, associationand/or interaction with β-arrestins.

In certain embodiments, the compounds of the invention diminish painwithout producing respiratory depression, such as that caused bymorphine and other well-known and widely used opioids and narcotics. Incertain embodiments, the compounds of the invention diminish painwithout producing constipation, such as that caused by morphine andother well-known and widely used opioids and narcotics. In certainembodiments, the compounds of the invention diminish pain withoutproducing nausea, such as that caused by morphine and other well-knownand widely used opioids and narcotics. In certain embodiments, thecompounds of the invention diminish pain without producing significant(or any at all) tolerance, such as that caused by morphine and otherwell-known and widely used opioids and narcotics. In certainembodiments, the compounds of the invention diminish pain withoutproducing significant (or any at all) tachyphylaxis, such as that causedby morphine and other well-known and widely used opioids and narcotics.In certain embodiments, the compounds of the invention diminish painwithout producing emesis, such as that caused by morphine and otherwell-known and widely used opioids and narcotics. In certainembodiments, the compounds of the invention diminish pain withoutproducing adverse effects associated with withdrawal, such as thatcaused by morphine and other well-known and widely used opioids andnarcotics. In certain embodiments, the compounds of the inventiondiminish pain without producing dependence, such as that caused bymorphine and other well-known and widely used opioids and narcotics. Incertain embodiments, the compounds of the invention diminish painwithout producing one or more of the following phenomena: nausea,emesis, constipation, respiratory depression, tolerance, tachyphylaxis,dependence and/or addiction.

The invention further provides methods of administering a compound ofthe invention to provide pain relief. In certain embodiments, the paincomprises chronic pain. In other embodiments, the pain comprisesneuropathic pain. In yet other embodiments, the pain comprisesnociceptive pain. In yet other embodiments, the pain compriseshyperalgesia. In yet other embodiments, the pain comprises allodynia.

Prior to the present day understanding of the β-arrestin pathways, manyGPCR ligands were developed pursuing optimization of 7-transmembrane(7-TM) receptor binding and not surprisingly, many widely usedtherapeutics are now known to be promiscuous, engaging both G-proteinand β-arrestin pathways. For example, morphine, the classic, prototypicmu opioid receptor agonist, produces analgesia through G-proteinsignaling. However, this effect is therapeutically ‘offset’ byβ-arrestin driven effects that produce receptor internalization anddesensitization, which result in tolerance that necessitates increasingdoses to maintain analgesic effect. In addition, β-arrestin drivensignaling leads to the production of side effects such as constipationand respiratory depression.

Consistently, mice lacking β-arrestin2 exhibit enhanced and prolongedanalgesia with very little tolerance, as well as attenuated respiratorydepression and acute constipation, as compared to wild type. Thisprovides evidence that MOR agonists that are selective for G-proteinsignaling, but devoid of β-arrestin-mediated effects, can providemorphine-like analgesia without the classic adverse effect profile. Thebiased MOR agonist, oliceridine or N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine,which is selective for G-protein signaling (EC₅₀=8 nM, E_(max)=83% vsmorphine) with only minor β-arrestin recruitment (14% E_(max)) incell-based assays, exhibited decreased on-target adverse effects (suchas nausea, and decrease in respiratory drive) in healthy volunteers andproduced a higher level of analgesia in patients following bunionectomy.This work demonstrates the power of biased ligands for GPCR signaling,which maintain/enhance desired therapeutic benefits while removingadverse side effects.

In certain embodiments, the ability of a compound to activate G-proteinor β-arrestin is not an on/off switch for a given pathway, but rather acontinuous function. To capture this, each compound is measured foractivity in cell assays that are linked to β-arrestin recruitment andG-protein signaling. By comparing the activity between these twomeasures (accounting for both EC₅₀ and maximal response reached,E_(max)) a relative activity (RA) value is determined.

${\Delta {RA}} = {{{LOG}\left( \frac{EMAX_{\beta - {Arr}}}{EC50_{\beta - {Arr}}} \right)} - {{LOG}\; \left( \frac{EMAX_{G - {Protein}}}{EC50_{G - {Protein}}} \right)}}$

In the case of MOR it is desirable to have high activation of theG-protein pathway while reducing activation of β-arrestin. In the caseof the formula above, this means a lower RA.

Definitions

As used herein, each of the following terms has the meaning associatedwith it in this section. Unless defined otherwise, all technical andscientific terms used herein generally have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. Generally, the nomenclature used herein and the laboratoryprocedures in animal pharmacology, pharmaceutical science, separationscience, and organic chemistry are those well-known and commonlyemployed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e. to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.

As used herein, the term “about” is understood by persons of ordinaryskill in the art and varies to some extent on the context in which it isused. As used herein when referring to a measurable value such as anamount, a temporal duration, and the like, the term “about” is meant toencompass variations of ±20% or ±10%, more preferably ±5%, even morepreferably ±1%, and still more preferably ±0.1% from the specifiedvalue, as such variations are appropriate to perform the disclosedmethods.

In one aspect, the terms “co-administered” and “co-administration” asrelating to a subject refer to administering to the subject a compoundof the invention or salt thereof along with a compound that may alsotreat any disease or disorder contemplated herein and/or with a compoundthat is useful in treating other medical conditions but which inthemselves may cause or facilitate any disease or disorder contemplatedherein. In certain embodiments, the co-administered compounds areadministered separately, or in any kind of combination as part of asingle therapeutic approach. The co-administered compound may beformulated in any kind of combinations as mixtures of solids and liquidsunder a variety of solid, gel, and liquid formulations, and as asolution.

As used herein, the term “CYP450” as applied to enzymes refers tocytochrome P450 family of enzymes.

As used herein, a “disease” is a state of health of a subject whereinthe subject cannot maintain homeostasis, and wherein if the disease isnot ameliorated then the subject's health continues to deteriorate.

As used herein, a “disorder” in a subject is a state of health in whichthe subject is able to maintain homeostasis, but in which the subject'sstate of health is less favorable than it would be in the absence of thedisorder. Left untreated, a disorder does not necessarily cause afurther decrease in the subject's state of health.

As used herein, the term “ED₅₀” refers to the effective dose of aformulation that produces 50% of the maximal effect in subjects that areadministered that formulation.

As used herein, an “effective amount,” “therapeutically effectiveamount” or “pharmaceutically effective amount” of a compound is thatamount of compound that is sufficient to provide a beneficial effect tothe subject to which the compound is administered.

“Instructional material,” as that term is used herein, includes apublication, a recording, a diagram, or any other medium of expressionthat can be used to communicate the usefulness of the composition and/orcompound of the invention in a kit. The instructional material of thekit may, for example, be affixed to a container that contains thecompound and/or composition of the invention or be shipped together witha container that contains the compound and/or composition.Alternatively, the instructional material may be shipped separately fromthe container with the intention that the recipient uses theinstructional material and the compound cooperatively. Delivery of theinstructional material may be, for example, by physical delivery of thepublication or other medium of expression communicating the usefulnessof the kit, or may alternatively be achieved by electronic transmission,for example by means of a computer, such as by electronic mail, ordownload from a website.

As used herein, the term “pharmaceutical composition” or “composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a subject.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound useful within theinvention, and is relatively non-toxic, i.e., the material may beadministered to a subject without causing undesirable biological effectsor interacting in a deleterious manner with any of the components of thecomposition in which it is contained.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the subject such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the subject. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations. As used herein, “pharmaceuticallyacceptable carrier” also includes any and all coatings, antibacterialand antifungal agents, and absorption delaying agents, and the like thatare compatible with the activity of the compound useful within theinvention, and are physiologically acceptable to the subject.Supplementary active compounds may also be incorporated into thecompositions. The “pharmaceutically acceptable carrier” may furtherinclude a pharmaceutically acceptable salt of the compound useful withinthe invention. Other additional ingredients that may be included in thepharmaceutical compositions used in the practice of the invention areknown in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference.

As used herein, the language “pharmaceutically acceptable salt” refersto a salt of the administered compound prepared from pharmaceuticallyacceptable non-toxic acids and bases, including inorganic acids,inorganic bases, organic acids, inorganic bases, solvates, hydrates, andclathrates thereof.

The term “prevent,” “preventing” or “prevention,” as used herein, meansavoiding or delaying the onset of symptoms associated with a disease orcondition in a subject that has not developed such symptoms at the timethe administering of an agent or compound commences. Disease, conditionand disorder are used interchangeably herein.

By the term “specifically bind” or “specifically binds,” as used herein,is meant that a first molecule preferentially binds to a second molecule(e.g., a particular receptor or enzyme), but does not necessarily bindonly to that second molecule.

As used herein, a “subject” may be a human or non-human mammal or abird. Non-human mammals include, for example, livestock and pets, suchas ovine, bovine, porcine, canine, feline and murine mammals. In certainembodiments, the subject is human.

The term “treat,” “treating” or “treatment,” as used herein, meansreducing the frequency or severity with which symptoms of a disease orcondition are experienced by a subject by virtue of administering anagent or compound to the subject.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁-C₁₀means one to ten carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. Most preferred is (C₁-C₆)alkyl, such as, but notlimited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl andcyclopropylmethyl.

As used herein, the term “alkylene” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branchedhydrocarbon group having the number of carbon atoms designated (i.e.,C₁-C₁₀ means one to ten carbon atoms) and includes straight, branchedchain, or cyclic substituent groups, wherein the group has two openvalencies. Examples include methylene, 1,2-ethylene, 1,1-ethylene,1,1-propylene, 1,2-propylene and 1,3-propylene.

As used herein, the term “cycloalkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a cyclic chain hydrocarbonhaving the number of carbon atoms designated (i.e., C₃-C₆ means a cyclicgroup comprising a ring group consisting of three to six carbon atoms)and includes straight, branched chain or cyclic substituent groups.Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Most preferred is (C₃-C₆)cycloalkyl, suchas, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

As used herein, the term “alkenyl,” employed alone or in combinationwith other terms, means, unless otherwise stated, a stablemono-unsaturated or di-unsaturated straight chain or branched chainhydrocarbon group having the stated number of carbon atoms. Examplesinclude vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl,1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. Afunctional group representing an alkene is exemplified by —CH₂—CH═CH₂.

As used herein, the term “alkynyl,” employed alone or in combinationwith other terms, means, unless otherwise stated, a stable straightchain or branched chain hydrocarbon group with a triple carbon-carbonbond, having the stated number of carbon atoms. Non-limiting examplesinclude ethynyl and propynyl, and the higher homologs and isomers. Theterm “propargylic” refers to a group exemplified by —CH₂—C≡CH. The term“homopropargylic” refers to a group exemplified by —CH₂CH₂—C≡CH. Theterm “substituted propargylic” refers to a group exemplified by—CR₂—C≡CR, wherein each occurrence of R is independently H, alkyl,substituted alkyl, alkenyl or substituted alkenyl, with the proviso thatat least one R group is not hydrogen. The term “substitutedhomopropargylic” refers to a group exemplified by —CR₂CR₂—C≡CR, whereineach occurrence of R is independently H, alkyl, substituted alkyl,alkenyl or substituted alkenyl, with the proviso that at least one Rgroup is not hydrogen.

As used herein, the term “substituted alkyl,” “substituted cycloalkyl,”“substituted alkenyl” or “substituted alkynyl” means alkyl, cycloalkyl,alkenyl or alkynyl, as defined above, substituted by one, two or threesubstituents selected from the group consisting of halogen, alkoxy,tetrahydro-2-H-pyranyl, —NH₂, —N(CH₃)₂, (1-methyl-imidazol-2-yl),pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, —C(═O)OH, trifluoromethyl,—C≡N, —C(═O)O(C₁-C₄)alkyl, —C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl,—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —C(═NH)NH₂, and —NO₂, preferablycontaining one or two substituents selected from halogen, —OH, alkoxy,—NH₂, trifluoromethyl, —N(CH₃)₂, and —C(═O)OH, more preferably selectedfrom halogen, alkoxy and —OH. Examples of substituted alkyls include,but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and3-chloropropyl. In certain embodiments, the substituted alkyl is notsubstituted with a hydroxy group.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined above, connected to therest of the molecule via an oxygen atom, such as, for example, methoxy,ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs andisomers. Preferred are (C₁-C₃)alkoxy, such as, but not limited to,ethoxy and methoxy.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “heteroalkyl” by itself or in combination withanother term means, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

As used herein, the term “heteroalkenyl” by itself or in combinationwith another term means, unless otherwise stated, a stable straight orbranched chain monounsaturated or di-unsaturated hydrocarbon groupconsisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. Up to two heteroatomsmay be placed consecutively. Examples include —CH═CH—O—CH₃,—CH═CH—CH₂—OH, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e. having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings)wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples includephenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, mostpreferred is phenyl.

As used herein, the term “aryl-(C₁-C₃)alkyl” means a functional groupwherein a one to three carbon alkylene chain is attached to an arylgroup, e.g., —CH₂CH₂-phenyl or —CH₂-phenyl (benzyl). Preferred isaryl-CH₂— and aryl-CH(CH₃)—. The term “substituted aryl-(C₁-C₃)alkyl”means an aryl-(C₁-C₃)alkyl functional group in which the aryl group issubstituted. Preferred is substituted aryl(CH₂)—. Similarly, the term“heteroaryl-(C₁-C₃)alkyl” means a functional group wherein a one tothree carbon alkylene chain is attached to a heteroaryl group, e.g.,—CH₂CH₂-pyridyl. Preferred is heteroaryl-(CH₂)—. The term “substitutedheteroaryl-(C₁-C₃)alkyl” means a heteroaryl-(C₁-C₃)alkyl functionalgroup in which the heteroaryl group is substituted. Preferred issubstituted heteroaryl-(CH₂)—.

As used herein, the term “heterocycle” or “heterocyclyl” or“heterocyclic” by itself or as part of another substituent means, unlessotherwise stated, an unsubstituted or substituted, stable, mono- ormulti-cyclic heterocyclic ring system that consists of carbon atoms andat least one heteroatom selected from the group consisting of N, O, andS, and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen atom may be optionally quaternized. Theheterocyclic system may be attached, unless otherwise stated, at anyheteroatom or carbon atom that affords a stable structure. A heterocyclemay be aromatic or non-aromatic in nature. In certain embodiments, theheterocycle is a heteroaryl.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includetetrahydroquinoline and 2,3-dihydrobenzofuryl.

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl(such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl,thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyland 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolinyl (such as, but not limited to, 1- and5-isoquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl,quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl),quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl,coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, butnot limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl,1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-,5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, butnot limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl,acridinyl, pyrrolizidinyl, and quinolizidinyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative and not limiting.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup.

For aryl, aryl-(C₁-C₃)alkyl and heterocyclyl groups, the term“substituted” as applied to the rings of these groups refers to anylevel of substitution, namely mono-, di-, tri-, tetra-, orpenta-substitution, where such substitution is permitted. Thesubstituents are independently selected, and substitution may be at anychemically accessible position. In certain embodiments, the substituentsvary in number between one and four. In other embodiments, thesubstituents vary in number between one and three. In yet otherembodiments, the substituents vary in number between one and two. In yetother embodiments, the substituents are independently selected from thegroup consisting of C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy, halo, amino, acetamidoand nitro. As used herein, where a substituent is an alkyl or alkoxygroup, the carbon chain may be branched, straight or cyclic, withstraight being preferred.

The following abbreviations are used herein: Ar, argon; β-arrestin,beta-arrestin-2 (protein); Boc₂O, di-tert-butyl dicarbonate; C, carbon;cAMP, cyclic adenosine monophosphate; CHCl₃, chloroform; DCM (orCH₂Cl₂), methylene chloride (dichloromethane); DIPEA,N,N-diisopropylethylamine; DMF, N,N-dimethylformamide; E_(MAX), maximalresponse reached; ESI, electrospray ionization; Et₂O, (di)ethyl ether;EtOAc, ethyl acetate; GCMS, gas chromatogram-mass spectrometry; H₂,hydrogen gas; HCl, hydrochloric acid; iPrOH, isopropanol; K₂CO₃,potassium carbonate; KOH, potassium hydroxide; LCMS, liquidchromatography - mass spectrometry; MeCN (or CH₃CN), acetonitrile; MHz,megahertz; MgSO₄, magnesium sulfate; MOR, mu opioid receptor; MS, massspectrometry; NaHCO₃, sodium bicarbonate; Na₂SO₄, sodium sulfate; nc,not calculated; nd, not done (not conducted); NMR, nuclear magneticresonance; Pd, palladium (metal); PE, petroleum ether; ppm, parts permillion; RA, relative activity; Ra/Ni, Raney Nickel; TEA,trimethylamine.

Throughout this disclosure, various aspects of the invention may bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible sub-ranges as well asindividual numerical values within that range and, when appropriate,partial integers of the numerical values within ranges. For example,description of a range such as from 1 to 6 should be considered to havespecifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well asindividual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5,5.3, and 6. This applies regardless of the breadth of the range.

Compounds and Compositions

The invention includes a compound of formula (I), or a salt, solvate,enantiomer, diastereoisomer and/or tautomer thereof:

wherein:

-   A is selected from the group consisting of

-   B¹ is selected from the group consisting of

and B² is H;

-   -   or B¹ and B² are independently selected from the group        consisting of —CH₃ and —CH₂CH₃, or    -   B¹ and B² combine to form a divalent substituent selected from        the group consisting of —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, and        —CH₂CH₂OCH₂CH₂—;

-   R¹ and R² are independently selected from the group consisting of H,    CH₃, and CH₃ substituted with at least one selected from the group    consisting of fluoro, chloro, cyano, hydroxyl, and nitro;

-   R³ is selected from the group consisting of H and CH₃;

-   X is selected from the group consisting of S, O, and N—R³, wherein    R^(3′) is selected from the group consisting of hydrogen, alkyl, and    substituted alkyl;

-   each occurrence of R is independently selected from the group    consisting of fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl,    alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, phenyl, and substituted phenyl;

-   each occurrence of m is independently selected from the group    consisting of 0, 1, 2, and 3;

-   n is selected from the group consisting of 1, 2, and 3; and

-   each occurrence of p is independently selected from the group    consisting of 0, 1, 2, and 3.

In certain embodiments, the alkyl is C₁-C₆ alkyl. In other embodiments,the substituted alkyl is C₁-C₆ alkyl substituted with at least oneselected from the group consisting of fluoro, chloro, bromo, iodo,cyano, nitro, and hydroxyl. In yet other embodiments, the alkenyl isC₂-C₆ alkenyl. In yet other embodiments, the substituted alkenyl isC₂-C₆ alkenyl substituted with at least one selected from the groupconsisting of hydrogen, alkyl, fluoro, chloro, phenyl, and substitutedphenyl. In yet other embodiments, the alkynyl is C₂-C₆ alkynyl. In yetother embodiments, the substituted alkynyl is C₂-C₆ alkynyl substitutedwith at least one selected from the group consisting of hydrogen, alkyl,phenyl, and substituted phenyl. In yet other embodiments, thesubstituted phenyl is phenyl substituted with at least one selected fromthe group consisting of alkyl, fluoro, chloro, bromo, iodo, cyano,nitro, hydroxyl, carboxylic acid, carboxylalkyl, and carboxamide.

In certain embodiments, A is isoindolin-2-yl. In other embodiments, A is5-fluoroisoindolin-2-yl. In yet other embodiments, A is5-chloroisoindolin-2-yl. In yet other embodiments, A is5-methoxyisoindolin-2-yl. In yet other embodiments, A is5-methylisoindolin-2-yl. In yet other embodiments, A is5-hydroxyisoindolin-2-yl. In yet other embodiments, A is5-cyanoisoindolin-2-yl. In other embodiments, A is4-fluoroisoindolin-2-yl. In yet other embodiments, A is4-chloroisoindolin-2-yl. In yet other embodiments, A is4-methoxyisoindolin-2-yl. In yet other embodiments, A is4-methylisoindolin-2-yl. In yet other embodiments, A is4-hydroxyisoindolin-2-yl. In yet other embodiments, A is 4-cyanoisoindolin-2-yl. In yet other embodiments, A is5,6-difluoroisoindolin-2-yl. In yet other embodiments, A is5,6-dichloroisoindolin-2-yl. In yet other embodiments, A is6-chloro-5-fluoroisoindolin-2-yl. In yet other embodiments, A is5-chloro-6-fluoroisoindolin-2-yl.

In certain embodiments, A is 1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 5-fluoro-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 8-fluoro-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 5-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 6-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 7-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl. In otherembodiments, A is 8-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl.

In certain embodiments, A is 1,2,3,4-tetrahydronaphthalen-1-yl-amino. Inother embodiments, A is 1,2,3,4-tetrahydronaphthalen-2-yl-amino. In yetother embodiments, A is5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-amino. In yet otherembodiments, A is 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-amino. Inyet other embodiments, A is 7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-amino. In yet other embodiments, A is8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl-amino. In yet otherembodiments, A is 5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl-amino. Inyet other embodiments, A is6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl-amino. In yet otherembodiments, A is 7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl-amino. Inyet other embodiments, A is8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl-amino. In yet otherembodiments, A is 5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl-amino. Inyet other embodiments, A is 6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl-amino. In yet other embodiments, A is7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl-amino. In yet otherembodiments, A is 8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl-amino. Inyet other embodiments, A is5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl-amino. In yet otherembodiments, A is 6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl-amino. Inyet other embodiments, A is7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl-amino. In yet otherembodiments, A is 8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl-amino.

In certain embodiments, A is 3-phenyl-pyrrolidin-1-yl. In otherembodiments, A is 3-substituted phenyl- pyrrolidin-1-yl.

In certain embodiments, B¹ is 3-thienyl. In other embodiments, B¹ is2-thienyl. In yet other embodiments, B¹ is 2-chloro-4-fluorophenyl. Inyet other embodiments, B¹ is 4-chloro-2-fluorophenyl. In yet otherembodiments, B¹ is 4-methoxyphenyl. In yet other embodiments, B¹ is4-hydroxyphenyl. In yet other embodiments, B¹ is phenyl. In yet otherembodiments, B² is H.

In certain embodiments, B¹ is —CH₃ and B² is —CH₃. In other embodiments,B¹ is —CH₃ and B² is —CH₂CH₃. In yet other embodiments, B¹ is —CH₂CH₃and B² is —CH₃. In yet other embodiments, B¹ is —CH₂CH₃ and B¹ is—CH₂CH₃.

In certain embodiments, B¹ and B² combine to form —CH₂CH₂CH₂CH₂—. Inother embodiments, B¹ and B² combine to form —CH₂CH₂CH₂CH₂CH₂—. In yetother embodiments, B¹ and B² combine to form —CH₂CH₂OCH₂CH₂—.

In certain embodiments, R is fluoro. In other embodiments, R is chloro.In yet other embodiments, R is bromo. In yet other embodiments, R isiodo. In yet other embodiments, R is cyano. In yet other embodiments, Ris nitro. In yet other embodiments, R is hydroxyl. In yet otherembodiments, R is alkyl. In yet other embodiments, R is substitutedalkyl. In yet other embodiments, R is alkenyl. In yet other embodiments,R is substituted alkenyl. In yet other embodiments, R is alkynyl. In yetother embodiments, R is substituted alkynyl. In yet other embodiments, Ris phenyl. In yet other embodiments, R is substituted phenyl.

In certain embodiments, in A at least one R is fluoro. In otherembodiments, in A at least one R is chloro. In yet other embodiments, inA at least one R is bromo. In yet other embodiments, in A at least one Ris iodo. In yet other embodiments, in A at least one R is cyano. In yetother embodiments, in A at least one R is nitro. In yet otherembodiments, in A at least one R is hydroxyl. In yet other embodiments,in A at least one R is alkyl. In yet other embodiments, in A at leastone R is substituted alkyl. In yet other embodiments, in A at least oneR is alkenyl. In yet other embodiments, in A at least one R issubstituted alkenyl. In yet other embodiments, in A at least one R isalkynyl. In yet other embodiments, in A at least one R is substitutedalkynyl. In yet other embodiments, in A at least one R is phenyl. In yetother embodiments, in A at least one R is substituted phenyl.

In certain embodiments, in B¹ at least one R is fluoro. In otherembodiments, in B¹ at least one R is chloro. In yet other embodiments,in B¹ at least one R is bromo. In yet other embodiments, in B¹ at leastone R is iodo. In yet other embodiments, in B¹ at least one R is cyano.In yet other embodiments, in B¹ at least one R is nitro. In yet otherembodiments, in B¹ at least one R is hydroxyl. In yet other embodiments,in B¹ at least one R is alkyl. In yet other embodiments, in B¹ at leastone R is substituted alkyl. In yet other embodiments, in B¹ at least oneR is alkenyl. In yet other embodiments, in B¹ at least one R issubstituted alkenyl. In yet other embodiments, in B¹ at least one R isalkynyl. In yet other embodiments, in B¹ at least one R is substitutedalkynyl. In yet other embodiments, in B¹ at least one R is phenyl. Inyet other embodiments, in B¹ at least one R is substituted phenyl.

In certain embodiments, R¹ is H. In other embodiments, R¹ is CH₃. In yetother embodiments, R² is H. In yet other embodiments, R² is CH₃.

In certain embodiments, m is 0. In other embodiments, m is 1. In otherembodiments, m is 2. In other embodiments, m is 3. In other embodiments,n is 1. In other embodiments, n is 2. In other embodiments, n is 3. Inother embodiments, p is 0. In other embodiments, p is 1. In otherembodiments, p is 2. In other embodiments, p is 3.

In certain embodiments, the compound of the invention is at least oneselected from the group consisting of:N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide;(−)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide;(+)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamide;5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-3,4-dihydroquinoline-1(2H)-carboxamide;1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methysoindoline-2-carboxamide;3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide;1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;N-(2-(Dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamide;3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;(R)-3-Phenyl-pyrrolidine-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;(S)-3-Phenyl-pyrrolidine-1-carboxylic acid acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;(S)-3-Phenyl-pyrrolidine-1-carboxylic acid acid[2-dimethylamino-2-(4-methoxy -phenyl)-ethyl]-amide;(R)-3-Phenyl-pyrrolidine-1-carboxylic acid[2-dimethylamino-2-(4-methoxy-phenyl)-ethyl]-amide;4-Cyano-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclohexylmethyl)-amide;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;7-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((R)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;1,3-Dihydro-isoindole-2-carboxylic acid (1-dimethylamino-cyclohexylmethyl)-amide;(R)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;(S)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;(−)-N-(2-(Dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide;(+)-N-(2-(Dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((S)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(4-dimethylamino-tetrahydro-pyran-4-ylmethyl)-amide;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-methyl-propyl)-amide;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclopentylmethyl)-amide;1,3-Dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclopentylmethyl)-amide;1-(1-Dimethylamino-cyclopentylmethyl)-3-(S)-1,2,3,4-tetrahydronaphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydronaphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydronaphthalen-2-yl-urea;N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-phenylethyl)-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-phenylethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-4S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;(R)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(S)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(S)—N—((S)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(−)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(+)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(−)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(+)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(−)-5-Fluoro-N-(2-(4-methoxyphenyl)-2-(methylamino)ethyl)isoindoline-2-carboxamide;(+)-5-Fluoro-N-(2-(4-methoxyphenyl)-2-(methylamino)ethyl)isoindoline-2-carboxamide;(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;(S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(4-hydroxyphenyl)ethyl-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-5-hydroxyisoindoline-2-carboxamide;N-(2-(dimethylamino)-2-(4-hydroxyphenyl)ethyl-5-hydroxyisoindoline-2-carboxamide;5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide;(−)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide;(+)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide; or asalt, solvate, enantiomer, diastereoisomer and/or tautomer thereof.

The compounds of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the (R) or (S)configuration. In certain embodiments, compounds described herein arepresent in optically active or racemic forms. It is to be understoodthat the compounds described herein encompass racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.Preparation of optically active forms is achieved in any suitablemanner, including by way of non-limiting example, by resolution of theracemic form with recrystallization techniques, synthesis fromoptically-active starting materials, chiral synthesis, orchromatographic separation using a chiral stationary phase. In certainembodiments, a mixture of one or more isomer is utilized as thetherapeutic compound described herein. In other embodiments, compoundsdescribed herein contain one or more chiral centers. These compounds areprepared by any means, including stereoselective synthesis,enantioselective synthesis and/or separation of a mixture of enantiomersand/ or diastereomers. Resolution of compounds and isomers thereof isachieved by any means including, by way of non-limiting example,chemical processes, enzymatic processes, fractional crystallization,distillation, and chromatography. All possible stereochemicalconfigurations of a given compound containing chiral center(s) arecontemplated. All possible mixtures enriched with a particularenantiomer or diasteromer(s) are contemplated. All pure individualenantiomers or diastereomers are contemplated.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),solvates, amorphous phases, and/or pharmaceutically acceptable salts ofcompounds having the structure of any compound of the invention, as wellas metabolites and active metabolites of these compounds having the sametype of activity. Solvates include water, ether (e.g., tetrahydrofuran,methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetatesand the like. In certain embodiments, the compounds described hereinexist in solvated forms with pharmaceutically acceptable solvents suchas water, and ethanol. In other embodiments, the compounds describedherein exist in unsolvated form.

In certain embodiments, the compounds of the invention may exist astautomers. “Tautomerization” is a form of isomerization involving themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible, (e.g. in solution), a chemical equilibriumof tautomers can be reached. One well known example of tautomerizationis between a ketone and its corresponding enol. Heterocycles may formtautomers such as the interconversion of pyrrolidinone andhydroxypyrrole. All tautomers are included within the scope of thecompounds presented herein.

In certain embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Inother embodiments, a prodrug is enzymatically metabolized by one or moresteps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

In certain embodiments, sites on, for example, the aromatic ring portionof compounds of the invention is susceptible to various metabolicreactions. Incorporation of appropriate substituents on the aromaticring structures may reduce, minimize or eliminate this metabolicpathway. In certain embodiments, the appropriate substituent to decreaseor eliminate the susceptibility of the aromatic ring to metabolicreactions is, by way of example only, a deuterium, a halogen, or analkyl group.

Compounds described herein also include isotopically labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In certain embodiments, isotopically labeledcompounds are useful in drug and/or substrate tissue distributionstudies. In other embodiments, substitution with heavier isotopes suchas deuterium affords greater metabolic stability (for example, increasedin vivo half-life or reduced dosage requirements). In yet otherembodiments, substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds are prepared by any suitable method or by processes using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

In certain embodiments, the compounds described herein are labeled byother means, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Compounds of the invention can in certain embodiments form acids orbases. In certain embodiments, the invention contemplates acid additionsalts. In other embodiments, the invention contemplates base additionsalts. In yet other embodiments, the invention contemplatespharmaceutically acceptable acid addition salts. In yet otherembodiments, the invention contemplates pharmaceutically acceptable baseaddition salts. Pharmaceutically acceptable salts refer to salts ofthose bases or acids that are not toxic or otherwise biologicallyundesirable.

Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids(including hydrogen phosphate and dihydrogen phosphate). Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, examples of which include formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic,glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, trifluoromethanesulfonic,2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium, lithium and copper, ironand zinc salts. Pharmaceutically acceptable base addition salts alsoinclude organic salts made from basic amines such as, for example,N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared from the corresponding compound by reacting,for example, the appropriate acid or base with the compound.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser & Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey & Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts,Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all ofwhich are incorporated by reference for such disclosure). Generalmethods for the preparation of compound as described herein are modifiedby the use of appropriate reagents and conditions, for the introductionof the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

In certain embodiments, reactive functional groups, such as hydroxyl,amino, imino, thio or carboxy groups, are protected in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In other embodiments, each protective group is removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. In certain embodiments, protective groups are removed by acid,base, reducing conditions (such as, for example, hydrogenolysis), and/oroxidative conditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and are used to protect carboxy andhydroxy reactive moieties in the presence of amino groups protected withCbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties areblocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl, in the presence of amines that are blocked with acidlabile groups, such as t-butyl carbamate, or with carbamates that areboth acid and base stable but hydrolytically removable. In certainembodiments, carboxylic acid and hydroxy reactive moieties are blockedwith hydrolytically removable protective groups such as the benzylgroup, while amine groups capable of hydrogen bonding with acids areblocked with base labile groups such as Fmoc. Carboxylic acid reactivemoieties are protected by conversion to simple ester compounds asexemplified herein, which include conversion to alkyl esters, or areblocked with oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups are blocked withfluoride labile silyl carbamates. Allyl blocking groups are useful inthe presence of acid- and base- protecting groups since the former arestable and are subsequently removed by metal or pi-acid catalysts. Forexample, an allyl-blocked carboxylic acid is deprotected with apalladium-catalyzed reaction in the presence of acid labile t-butylcarbamate or base-labile acetate amine protecting groups. Yet anotherform of protecting group is a resin to which a compound or intermediateis attached. As long as the residue is attached to the resin, thatfunctional group is blocked and does not react. Once released from theresin, the functional group is available to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene & Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, and Kocienski, ProtectiveGroups, Thieme Verlag, New York, N.Y., 1994, which are incorporatedherein by reference for such disclosure.

In certain embodiments, compounds of the invention can be preparedaccording to the following general schemes.

In certain embodiments, an isoindoline is reacted with a similaractivating agent, such as but not limited to,para-nitrophenyl-chloroformate to afford an electrophilic carbamate,which then undergoes coupling with aN¹,N¹-dialkyl-1-(aryl)ethane-1,2-diamine, such as but not limited toN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine (Scheme 1).

In certain embodiments, a N¹,N¹-dialkyl-1-(aryl)ethane-1,2-diamine, suchas but not limited to N¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamineis reacted with an activating agent, such as but not limited topara-nitrophenyl-chloroformate to afford an electrophilic carbamate,which undergoes coupling with an isoindoline (Scheme 2).

In certain embodiments, a tetrahydroquinoline is reacted with anactivating agent, such as but not limited topara-nitrophenyl-chloroformate, to afford an electrophilic carbamate,which undergoes coupling with aN¹,N¹-dialkyl-1-(aryl)ethane-1,2-diamine, such as but not limited toN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine (Scheme 3).

In certain embodiments, a N¹,N¹-dialkyl-1-(aryl)ethane-1,2-diamine, suchas but not limited toN′,N′-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine, is reacted with anactivating agent, such as but not limited topara-nitrophenyl-chloroformate, to afford an electrophilic carbamate,which undergoes coupling with a tetrahydroquinoline (Scheme 4).

In certain embodiments, an aminotetralin is reacted with an activatingagent, such as but not limited to para-nitrophenyl-chloroformate, toafford an electrophilic carbamate, which undergoes coupling with aN¹,N¹-dialkyl-1-(aryl)ethane-1,2-diamine, such as but not limited toN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine (Scheme 5).

In certain embodiments, a N¹,N¹-dialkyl-1-(aryl)ethane-1,2-diamine, suchas but not limited toN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine, is reacted with anactivating agent, such as but not limited topara-nitrophenyl-chloroformate, to afford an electrophilic carbamate,which undergoes coupling with an aminotetralin (Scheme 6).

In certain embodiments, an optically-pure (tert-butyl)sulfinamide (i) isreacted with an aryl-carboxaldehyde or aralkyl-carboxaldehyde, in thepresence of an organic base such as but not limited to pyrrolidine, toproduce a N-aralkylene-sulfinamide (ii). Subsequent reaction with the(carbon-based) anion of acetonitrile produces the diastereomericN-(2-cyano-1-(aryl)alkyl)-2-sulfinamide (iii) which are separated by amethod such as but not limited to chromatography or crystallization.Hydrolysis of the sulfinamide affords optically-enriched3-amino-3-aryl)propanenitrile (iv). Reductive alkylation, using forexample an aldehyde and a reducing agent, such as but not limited to(sodium) triacetoxyborohydride, affords the correspondingoptically-enriched 3-(dialkylamino)-3-aryl-propanenitrile (v). Treatmentof (v) with a strong reducing agent, such as but not limited to lithiumaluminum hydride, produces a N¹,N¹-dialkyl-1-(ayl)propane-1,3-diamine(vi). The diamine is activated by reaction with a chloroformate such asbut not limited to para-nitrophenyl chloroformate to afford carbamate(vii), which is reacted with an isoindoline, tetrahydroisoquinoline, oraminotetralin, to produce compounds of this invention (Scheme 7).

Administration/Dosage/Formulations

The invention also encompasses pharmaceutical compositions and methodsof their use. These pharmaceutical compositions may comprise an activeingredient (which can be one or more compounds of the invention, orpharmaceutically acceptable salts thereof) optionally in combinationwith one or more pharmaceutically acceptable agents. The compositionsset forth herein can be used alone or in combination with additionalcompounds to produce additive, complementary, or synergistic effects.

The regimen of administration may affect what constitutes an effectiveamount. The therapeutic formulations may be administered to the subjecteither prior to or after the onset of a disease or disorder contemplatedherein. Further, several divided dosages, as well as staggered dosagesmay be administered daily or sequentially, or the dose may becontinuously infused, or may be a bolus injection. Further, the dosagesof the therapeutic formulations may be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Administration of the compositions of the present invention to apatient, preferably a mammal, more preferably a human, may be carriedout using known procedures, at dosages and for periods of time effectiveto treat a disease or disorder contemplated herein. An effective amountof the therapeutic compound necessary to achieve a therapeutic effectmay vary according to factors such as the state of the disease ordisorder in the patient; the age, sex, and weight of the patient; andthe ability of the therapeutic compound to treat a disease or disordercontemplated herein. Dosage regimens may be adjusted to provide theoptimum therapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A non-limitingexample of an effective dose range for a therapeutic compound of theinvention is from about 1 and 5,000 mg/kg of body weight/per day. One ofordinary skill in the art would be able to study the relevant factorsand make the determination regarding the effective amount of thetherapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level depends upon a variety offactors including the activity of the particular compound employed, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds or materials used incombination with the compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skillin the art may readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower than thatrequired in order to achieve the desired therapeutic effect, andgradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a therapeutic compound for thetreatment of a disease or disorder contemplated herein.

In certain embodiments, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Incertain embodiments, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of a compound of theinvention and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity may be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms may be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it is preferable to include isotonic agents, for example, sugars,sodium chloride, or polyalcohols such as mannitol and sorbitol, in thecomposition. Prolonged absorption of the injectable compositions may bebrought about by including in the composition an agent that delaysabsorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the compositions of the invention areadministered to the patient in dosages that range from one to five timesper day or more. In other embodiments, the compositions of the inventionare administered to the patient in range of dosages that include, butare not limited to, once every day, every two, days, every three days toonce a week, and once every two weeks. It is readily apparent to oneskilled in the art that the frequency of administration of the variouscombination compositions of the invention varies from individual toindividual depending on many factors including, but not limited to, age,disease or disorder to be treated, gender, overall health, and otherfactors. Thus, the invention should not be construed to be limited toany particular dosage regime and the precise dosage and composition tobe administered to any patient is determined by the attending physicaltaking all other factors about the patient into account.

Compounds of the invention for administration may be in the range offrom about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg toabout 7,500 mg, about 200 μg to about 7,000 mg, about 350 μg to about6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg toabout 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80mg to about 500 mg, and any and all whole or partial increments therebetween.

In certain embodiments, the dose of a compound of the invention is fromabout 1 mg and about 2,500 mg. In other embodiments, a dose of acompound of the invention used in compositions described herein is lessthan about 10,000 mg, or less than about 8,000 mg, or less than about6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, orless than about 2,000 mg, or less than about 1,000 mg, or less thanabout 500 mg, or less than about 200 mg, or less than about 50 mg.Similarly, in other embodiments, a dose of a second compound asdescribed herein is less than about 1,000 mg, or less than about 800 mg,or less than about 600 mg, or less than about 500 mg, or less than about400 mg, or less than about 300 mg, or less than about 200 mg, or lessthan about 100 mg, or less than about 50 mg, or less than about 40 mg,or less than about 30 mg, or less than about 25 mg, or less than about20 mg, or less than about 15 mg, or less than about 10 mg, or less thanabout 5 mg, or less than about 2 mg, or less than about 1 mg, or lessthan about 0.5 mg, and any and all whole or partial increments thereof.

In certain embodiments, the present invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a compound of the invention, aloneor in combination with a second pharmaceutical agent; and instructionsfor using the compound to treat, prevent, or reduce one or more symptomsof a disease or disorder contemplated herein.

Formulations may be employed in admixtures with conventional excipients,i.e., pharmaceutically acceptable organic or inorganic carriersubstances suitable for oral, parenteral, nasal, intravenous,subcutaneous, enteral, or any other suitable mode of administration,known to the art. The pharmaceutical preparations may be sterilized andif desired mixed with auxiliary agents, e.g., lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure buffers, coloring, flavoring and/or aromatic substances and thelike. They may also be combined where desired with other active agents,e.g., other analgesic agents.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,sublingual or topical. The compounds for use in the invention may beformulated for administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- andperivaginally), (intra)nasal and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically excipients that are suitable for the manufacture oftablets. Such excipients include, for example an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by knowntechniques for elegance or to delay the release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

For oral administration, the compounds of the invention may be in theform of tablets or capsules prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.,polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc, or silica); disintegrates (e.g., sodium starch glycollate); orwetting agents (e.g., sodium lauryl sulphate). If desired, the tabletsmay be coated using suitable methods and coating materials such asOPADRY™ film coating systems available from Colorcon, West Point, Pa.(e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, AqueousEnteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquidpreparation for oral administration may be in the form of solutions,syrups or suspensions. The liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, methyl cellulose orhydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia);non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol);and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbicacid).

Granulating techniques are well known in the pharmaceutical art formodifying starting powders or other particulate materials of an activeingredient. The powders are typically mixed with a binder material intolarger permanent free-flowing agglomerates or granules referred to as a“granulation.” For example, solvent-using “wet” granulation processesare generally characterized in that the powders are combined with abinder material and moistened with water or an organic solvent underconditions resulting in the formation of a wet granulated mass fromwhich the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that aresolid or semi-solid at room temperature (i.e. having a relatively lowsoftening or melting point range) to promote granulation of powdered orother materials, essentially in the absence of added water or otherliquid solvents. The low melting solids, when heated to a temperature inthe melting point range, liquefy to act as a binder or granulatingmedium. The liquefied solid spreads itself over the surface of powderedmaterials with which it is contacted, and on cooling, forms a solidgranulated mass in which the initial materials are bound together. Theresulting melt granulation may then be provided to a tablet press or beencapsulated for preparing the oral dosage form. Melt granulationimproves the dissolution rate and bioavailability of an active (i.e.drug) by forming a solid dispersion or solid solution.

U.S. Pat. No. 5,169,645 discloses directly compressible wax-containinggranules having improved flow properties. The granules are obtained whenwaxes are admixed in the melt with certain flow improving additives,followed by cooling and granulation of the admixture. In certainembodiments, only the wax itself melts in the melt combination of thewax(es) and additives(s), and in other cases both the wax(es) and theadditives(s) melt.

The present invention also includes a multi-layer tablet comprising alayer providing for the delayed release of one or more compounds of theinvention, and a further layer providing for the immediate release of amedication for treatment of diseases or disorders. Using awax/pH-sensitive polymer mix, a gastric insoluble composition may beobtained in which the active ingredient is entrapped, ensuring itsdelayed release.

Parenteral Administration

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose and/or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizingand/or dispersing agents may be used.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms asdescribed in U.S. Pat. Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389;5,582,837; and 5,007,790. Additional dosage forms of this invention alsoinclude dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and20020051820. Additional dosage forms of this invention also includedosage forms as described in PCT Applications Nos. WO 03/35041; WO03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems

In certain embodiments, the formulations of the present invention maybe, but are not limited to, short-term, rapid-offset, as well ascontrolled, for example, sustained release, delayed release andpulsatile release formulations.

The term sustained release is used in its conventional sense to refer toa drug formulation that provides for gradual release of a drug over anextended period of time, and that may, although not necessarily, resultin substantially constant blood levels of a drug over an extended timeperiod. The period of time may be as long as a month or more and shouldbe a release that is longer that the same amount of agent administeredin bolus form.

For sustained release, the compounds may be formulated with a suitablepolymer or hydrophobic material that provides sustained releaseproperties to the compounds. As such, the compounds for use the methodof the invention may be administered in the form of microparticles, forexample, by injection or in the form of wafers or discs by implantation.

In certain embodiments, the compounds of the invention are administeredto a patient, alone or in combination with another pharmaceutical agent,using a sustained release formulation.

The term delayed release is used herein in its conventional sense torefer to a drug formulation that provides for an initial release of thedrug after some delay following drug administration and that mat,although not necessarily, includes a delay of from about 10 minutes upto about 12 hours.

The term pulsatile release is used herein in its conventional sense torefer to a drug formulation that provides release of the drug in such away as to produce pulsed plasma profiles of the drug after drugadministration.

The term immediate release is used in its conventional sense to refer toa drug formulation that provides for release of the drug immediatelyafter drug administration.

As used herein, short-term refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes and any or all whole orpartial increments thereof after drug administration after drugadministration.

As used herein, rapid-offset refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes, and any and all whole orpartial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound of thepresent invention depends on the age, sex and weight of the patient, thecurrent medical condition of the patient and the progression of adisease or disorder contemplated herein in the patient being treated.The skilled artisan is able to determine appropriate dosages dependingon these and other factors.

A suitable dose of a compound of the present invention may be in therange of from about 0.01 mg to about 5,000 mg per day, such as fromabout 0.1 mg to about 1,000 mg, for example, from about 1 mg to about500 mg, such as about 5 mg to about 250 mg per day. The dose may beadministered in a single dosage or in multiple dosages, for example from1 to 4 or more times per day. When multiple dosages are used, the amountof each dosage may be the same or different. For example, a dose of 1 mgper day may be administered as two 0.5 mg doses, with about a 12-hourinterval between doses.

It is understood that the amount of compound dosed per day may beadministered, in non-limiting examples, every day, every other day,every 2 days, every 3 days, every 4 days, or every 5 days. For example,with every other day administration, a 5 mg per day dose may beinitiated on Monday with a first subsequent 5 mg per day doseadministered on Wednesday, a second subsequent 5 mg per day doseadministered on Friday, and so on.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the inhibitor of the invention isoptionally given continuously; alternatively, the dose of drug beingadministered is temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug holiday”). The length of the drugholiday optionally varies between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, or 365 days. The dose reduction during a drugholiday includes from 10%-100%, including, by way of example only, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is reduced, as a function of theviral load, to a level at which the improved disease is retained. Incertain embodiments, patients require intermittent treatment on along-term basis upon any recurrence of symptoms and/or infection.

The compounds for use in the method of the invention may be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for patients undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form may be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form may be the same or different foreach dose.

Toxicity and therapeutic efficacy of such therapeutic regimens areoptionally determined in cell cultures or experimental animals,including, but not limited to, the determination of the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between the toxicand therapeutic effects is the therapeutic index, which is expressed asthe ratio between LD₅₀ and ED₅₀. The data obtained from cell cultureassays and animal studies are optionally used in formulating a range ofdosage for use in human. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED₅₀ withminimal toxicity. The dosage optionally varies within this rangedepending upon the dosage form employed and the route of administrationutilized.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXPERIMENTAL EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only and theinvention should in no way be construed as being limited to theseExamples, but rather should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. The following workingexamples therefore, specifically point out the preferred embodiments ofthe present invention, and are not to be construed as limiting in anyway the remainder of the disclosure.

Example 1 G-Protein Assay Measuring cAMP

G-protein signaling was measured via second messenger cAMP modulation.Detection of cAMP modulation was accomplished in the PathHunter humanOPRM1 (μ, MOR) Arrestin CHO-K1 cell line using the Dynamic2 cAMP Kitfrom Cisbio. The E_(MAX) values of the chemiluminescent signal are allnormalized to DAMGO, which is defined as 100%.

Example 2 β-Arrestin Assay

The Discoverx PathHunter® β-Arrestin assay is used to measureβ-arrestin-2 activity. The technology is based on Enzyme FragmentComplementation (EFC) with (3-galactosidase (β-Gal) as the reporter. Theenzyme is split into two inactive complementary portions (EA for EnzymeAcceptor, and ED for Enzyme Donor) expressed as fusion proteins in thecell. EA is fused to β-arrestin-2, and ED is fused to the C-terminus ofthe GPCR of interest. When a ligand binds and the GPCR is activated,β-arrestin-2 is recruited to the receptor resulting in an ED/EAcomplementation, restoring P-Gal activity, which is measured usingchemiluminescence. For this assay, the PathHunter human OPRM1 (μ, MOR)Arrestin CHO-K1 cell line was used. The E_(MAX) values of thechemiluminescent signal were all normalized to DAMGO, which is definedas 100%.

Example 3N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-isoindoline-2-carboxamide(1) and corresponding hydrochloride salt (1a)

(a)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(1)

A mixture of N¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine (150 mg,0.88 mmol) and N,N-diisopropylethylamine (180 μL, 1.05 mmol) in CH₂Cl₂(10 mL) was purged with argon and cooled to 0° C. A solution of4-nitrophenylchloroformate (213 mg, 1.05 mmol) in CH₂Cl₂ (5 mL) wasadded and resulting solution was stirred at 0° C. for 1 h. After thistime, isoindoline hydrochloride (137 mg, 0.88 mmol) was added followedby N,N-diisopropylethylamine (300 μL, 1.77 mmol), and the resultingmixture was stirred for 16 h at room temperature. A saturated NaHCO₃solution (10 mL) was added and the resulting suspension was extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were washed withwater (30 mL) and then dried over solid anhydrous MgSO₄. Afterfiltration, the volatiles were removed, and the residue was was purifiedby flash chromatography using eluent from CH₂Cl₂ to CH₂Cl₂/MeOH (10:1)to give N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide (1) as an oil (170 mg, 61% yield). 300 MHz¹H-NMR (CDCl₃, ppm): 7.31 (dd, J=5.0, 3.0 Hz, 1H) 7.28-7.23 (m, 4H) 7.10(dd, J=3.0, 1.3 Hz, 1H) 7.01 (dd, J=5.0, 1.3 Hz, 1H) 5.01-4.89 (m, 1H)4.73-4.56 (m, 4H) 3.74-3.63 (m, 2H) 3.61-3.49 (m, 1H) 2.21 (s, 6H).ESI-MS (m/z): 316 [M+H]⁺.

(b)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (1a)

A 2M HCl/diethyl ether (260 μL, 0.51 mmol) was added to the solution ofN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(1) (160 mg, 0.51 mmol) in diethyl ether/MeOH (45 mL/0.5 mL). Themixture was stirred for 2 h at ambient temperature. The resultantprecipitate were filtered and dried over P₂O₅ in vacuo at 65° C. for 24h to giveN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (1a) (140 mg, 78% yield). 400 MHz ¹H-NMR (CD₃OD, ppm):7.85-7.79 (m, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H) 7.35-7.28 (m, 5H)4.78-4.65 (m, 5H) 4.13 (dd, J=15.1, 8.9 Hz, 1H) 3.65 (dd, J=15.1, 4.8Hz, 1H) 2.95-2.70 (m, 6H). ESI-MS (m/z): 316 [M+H]⁺; melting point:145-150° C. (dec.).

Example 4N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide(2) and corresponding hydrochloride salt (2a)

A mixture of N¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine (300 mg,1.76 mmol) and N,N-diisopropylethylamine (360 μL, 2.11 mmol) in CH₂Cl₂(10 mL) was purged with argon and cooled to 0 C. A solution of4-nitrophenylchloroformate (2) (426 mg, 2.11 mmol) in CH₂Cl₂ (5 mL) wasadded and resulting solution was stirred at 0° C. for 1 h. After thistime, 5-fluoroisoindoline hydrochloride (306 mg, 1.76 mmol) was added,followed by N,N-diisopropylethylamine (610 μL, 3.52 mmol), and theresulting mixture was stirred for 16 h at room temperature. A saturatedNaHCO₃ solution (10 mL) was added and the resulting suspension wasextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts werewashed with water (30 mL) and dried over solid anhydrous MgSO₄. Afterfiltration, the volatiles were removed, and the residue was was purifiedby flash chromatography using eluent from CH₂Cl₂ to CH₂Cl₂/MeOH (10:1)to give crude product as a colorless foam. This material was solidifiedwith dry ethyl ether to give purerac-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide(2) as gray powder (300 mg, 51% yield). 300 MHz ¹H-NMR (CDCl₃, ppm):7.32 (dd, J=5.0, 3.0 Hz, 1H) 7.24-7.17 (m, 1H) 7.11 (dd, J=3.0, 1.3 Hz,1H) 7.02 (dd, J=5.0, 1.3 Hz, 1H) 6.99-6.92 (m, 2H) 5.03-4.87 (m, 1H)4.72-4.55 (m, 4H) 3.77-3.49 (m, 3H) 2.21 (s, 6H). ESI-MS (m/z): 334[M+H]⁺.

Example 5(−)-ent-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide(2-ent-(−)) and corresponding hydrochloride salt (2a-ent-(−)) Example 6(+)-ent-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide(2-ent-(+)) and corresponding hydrochloride salt (2a-ent-(+))

(a)(−)-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide(2-ent-(−)) and(+)-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide(2-ent-(+))

rac-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide(2) was separated into its enantiomers on a chiral stationary phasechromatography using (Daicel Chiralpak® AY-H 250 mm×10 mm) column andHex/EtOH (7:3) as mobile phase on Shimadzu LC-8A to obtain(−)-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide(2-ent-(−)) and(+)-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide(2-ent-(+)). Rt-(−) enantiomer=58 min, Rt-(+) enantiomer=82 min at1mL/min flow rate.

(b)(−)-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (2a-ent-(−))

A solution of 2M HCl/diethyl ether (75 μL, 0.15 mmol) was added to thesolution of(−)-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide(2-ent-(−)) (50 mg, 0.15 mmol) in diethyl ether/MeOH (20 mL/0.5 mL). Themixture was stirred for 2 h at ambient temperature and the resultantprecipitate was filtered and dried over P₂O₅ in vacuo at 65° C. for 24 hto give(−)-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (2a-ent-(−)) (45 mg, 81% yield). 400 MHz 1H-NMR (CD₃OD,ppm): 7.82 (dd, J=2.9, 1.4 Hz, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H)7.36-7.30 (m, 2H) 7.12-7.02 (m, 2H) 4.74 (dd, J=8.8, 4.7 Hz, 1H)4.78-4.62 (m, 4H) 4.12 (dd, J=15.1, 8.8 Hz, 1H) 3.65 (dd, J=15.1, 4.7Hz, 1H) 2.88 (s, 3H) 2.77 (s, 3H). ESI-MS (m/z): 334 [M+H]⁺; meltingpoint: 150-155° C. (dec.).

(c)(+)-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (2a-ent-(+))

A solution of 2M HCl/diethyl ether (60 μL, 0.12 mmol) was added to thesolution of(+)-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-fluoroisoindoline-2-carboxamide(2a-ent-(+)) (40 mg, 0.12 mmol) in diethyl ether/MeOH (15 mL/0.5 mL).The mixture was stirred for 2 h at ambient temperature and the resultantprecipitate were filtered and dried over P₂O₅ in vacuo at 65° C. for 24h to give(+)-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (2a-ent-(+) (35 mg, 79% yield). 400 MHz 1H-NMR (CD₃OD,ppm): 7.81 (dd, J=2.9, 1.4 Hz, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H)7.35-7.29 (m, 2H) 7.12-7.02 (m, 2H) 4.74 (dd, J=8.8, 4.7 Hz, 1H)4.78-4.62 (m, 4H) 4.12 (dd, J=15.1, 8.8 Hz, 1H) 3.65 (dd, J=15.1, 4.7Hz, 1H) 2.88 (s, 3H) 2.78 (s, 3H). ESI-MS (m/z): 334 [M+H]⁺; meltingpoint: 150-155° C. (dec.).

Example 7N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-4-fluoroisoindoline-2-carboxamide(3) and corresponding hydrochloride salt (3a)

(a)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamide(3)

4-Fluoroisoindoline hydrochloride (183 mg, 1.05 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to affordN-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-4-fluoroisoindoline-2-carboxamide(3) (120 mg, 41% yield). ESI-MS (m/z): 334 [M+H]⁺

(b)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamidehydrochloride (3a)

N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-4-fluoroisoindoline-2-carboxamide(3) (125 mg, 0.37 mmol) was treated with 2M HCl/diethyl ether in diethylether/MeOH (20 mL/0.5 mL) using procedure described for compound (1a) toproduceN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamidehydrochloride (3a). 400 MHz ¹-H-NMR (CD₃OD, ppm): 7.82 (dd, J=2.9, 1.4Hz, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H) 7.39-7.30 (m, 1H) 7.32 (dd, J=5.0,1.4 Hz, 1H) 7.18-7.12 (m, 1H) 7.07-7.00 (m, 1H) 4.82-4.65 (m, 5H) 4.12(dd, J=15.1, 9.0 Hz, 1H) 3.65 (dd, J=15.1, 4.9 Hz, 1H) 2.83 (s, 6H).ESI-MS (m/z): 334 [M+H]⁺; melting point: 150-155° C. (dec.).

Example 85-chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(4) and corresponding hydrochloride salt 4(a)

(a)5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(4)

5-Chloroisoindoline hydrochloride (167 mg, 0.88 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to afford5-chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(4) (110 mg, 36% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.33 (dd, J=5.0,2.9 Hz, 1H) 7.28-7.23 (m, 2H) 7.21-7.17 (m, 1H) 7.14-7.10 (m, 1H) 7.02(dd, J=5.0, 1.3 Hz, 1H) 5.05-4.91 (m, 1H) 4.72-4.57 (m, 4H) 3.78-3.63(m, 2H) 3.62-3.52 (m, 1H) 2.24 (s, 6H).

ESI-MS (m/z): 350, 352 [M+H]⁺

(b)5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (4a)

5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(4) (90 mg, 0.26 mmol) was treated with 2M HCl/diethyl ether in diethylether/MeOH (20 mL/3 mL) using procedure described for compound (1a) toproduce5-chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (4a) (85 mg, 85% yield). 400 MHz ¹H-NMR (CD₃OD, ppm):7.85-7.79 (m, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H) 7.38-7.35 (m, 1H)7.34-7.29 (m, 3H) 4.76-4.62 (m, 5H) 4.11 (dd, J=15.0, 8.7 Hz, 1H) 3.65(dd, J=15.0, 4.9 Hz, 1H) 2.82 (s, 6H). ESI-MS (m/z): 350, 352 [M+H]⁺;melting point: 210-215° C. (dec.).

Example 9N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide(5) and corresponding hydrochloride salt (5a)

(a)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide(5)

5-Methoxyisoindoline hydrochloride (163 mg, 0.88 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide(5) (190 mg, 62% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.32 (dd, J=5.0,2.9 Hz, 1H) 7.15 (d, J=8.3 Hz, 1H) 7.12 (dd, J=2.9, 1.3 Hz, 1H) 7.02(dd, J=5.0, 1.3 Hz, 1H) 6.83 (dd, J=8.3, 2.5 Hz, 1H) 6.79 (d, J=2.5 Hz,1H) 5.03-4.94 (m, 1H) 4.71-4.53 (m, 4H) 3.80 (s, 3H) 3.75-3.70 (m, 1H)3.67 (dd, J=8.7, 3.8 Hz, 1H) 3.59-3.52 (m, 1H) 2.22 (s, 6H). ESI-MS(m/z): 346[M+H]⁺

(b)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamidehydrochloride (5a)

N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide(5) (135 mg, 0.39 mmol) was treated with 2M HCl/diethyl ether in diethylether/MeOH (25 mL/5 mL) using procedure described for compound (1a) toproduceN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamidehydrochloride (5a) (102 mg, 68% yield). 400 MHz ¹H-NMR (CD₃OD, ppm):7.82 (dd, J=2.9, 1.4 Hz, 1H) 7.66 (dd, J=5.1, 2.9 Hz, 1H) 7.32 (dd,J=5.1, 1.4 Hz, 1H) 7.23-7.18 (m, 1H) 6.90-6.85 (m, 2H) 4.75 (dd, J=9.0,4.8 Hz, 1H) 4.72-4.57 (m, 4H) 4.12 (dd, J=15.1, 9.0 Hz, 1H) 3.79 (s, 3H)3.65 (dd, J=15.1, 4.8 Hz, 1H) 2.88 (s, 3H) 2.78 (s, 3H). ESI-MS (m/z):346[M+H]⁺; melting point: 210-215° C. (dec.).

Example 10N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5,6-difluoroisoindoline-2-carboxamide(6) and corresponding hydrochloride salt (6a)

(a)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide(6)

5,6-Difluoroisoindoline hydrochloride (150 mg, 0.78 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide(6) (90 mg, 33% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.32 (dd, J=4.9,2.9 Hz, 1H) 7.11 (dd, J=2.9, 1.2 Hz, 1H) 7.07 (dd, J=8.5, 8.5 Hz, 2H)7.01 (dd, J=5.0, 1.2 Hz, 1H) 4.98-4.91 (m, 1H) 4.66-4.57 (m, 4H)3.73-3.61 (m, 2H) 3.59-3.52 (m, 1H) 2.20 (s, 6H). ESI-MS (m/z): 352[M+H]⁺.

(b)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamidehydrochloride (6a)

5,6-Difluoro-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide (6) (85 mg, 0.24 mmol) wastreated with 2M HCl/diethyl ether in diethyl ether using proceduredescribed for compound (1a) to produceN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamidehydrochloride (6a) (80 mg, 85% yield). 400 MHz ¹H-NMR (CD₃OD, ppm): 7.80(dd, J=2.9, 1.2 Hz, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H) 7.32 (dd, J=5.0,1.2 Hz, 1H) 7.26 (dd, J=8.8, 8.8 Hz, 2H) 4.73 (dd, J=8.8, 4.9 Hz, 1H)4.67 (s, 4H) 4.11 (dd, J=15.1, 8.8 Hz, 1H) 3.65 (dd, J=15.1, 4.9 Hz, 1H)2.82 (s, 6H).

ESI-MS (m/z): 352 [M+H]⁺; melting point: 210-212° C.

Example 11N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(7) and corresponding hydrochloride salt (7a)

(a)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide(7)

6-Fluoro-1,2,3,4-tetrahydroquinoline hydrochloride (165 mg, 0.88 mmol)and N¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide(7) (120 mg, 39% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.31 (dd, J=5.0,2.9 Hz, 1H) 7.09-7.04 (m, 1H) 7.00-6.92 (m, 2H) 6.83 (dd, J=8.9, 2.9 Hz,1H) 6.75 (ddd, J=8.5, 8.5, 3.0 Hz, 1H) 5.43 (s, 1H) 3.77-3.61 (m, 4H)3.53-3.46 (m, 1H, 2.70 (t, J=6.7 Hz, 2H) 2.17 (s, 6H) 1.93-1.84 (m, 2H).ESI-MS (m/z): 348 [M+H]+.

(b)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamidehydrochloride (7a)

N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-3,4-dihydroquinoline-1(2H)-carboxamide(7) (120 mg, 0.35 mmol) was treated with 2M HCl/diethyl ether in diethylether using procedure described for compound (1a) to produceN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamidehydrochloride (7a) (133 mg, 100% yield). 400 MHz ¹H-NMR (DMSO-d₆, ppm):10.48 (s, 1H) 7.86 (dd, J=2.9, 0.9 Hz, 1H) 7.71 (dd, J=5.0, 2.9 Hz, 1H)7.37 (dd, J=5.0, 0.9 Hz, 1H) 7.27 (dd, J=9.0, 5.4 Hz, 1H) 7.01 (t, J=5.4Hz, 1H) 6.95 (dd, J=9.3, 3.0 Hz, 1H) 6.87 (ddd, J=8.7, 8.7, 3.0 Hz, 1H)4.74-4.65 (m, 1H) 3.98-3.86 (m, 1H) 3.65-3.48 (m, 3H) 2.74 (d, J=4.4 Hz,3H) 2.66 (t, J=6.3 Hz, 2H) 2.59 (d, J=4.4 Hz, 3H) 1.82-1.72 (m, 2H).ESI-MS (m/z): 348 [M+H]+.

Example 12N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(8) and corresponding hydrochloride salt (8a)

(a)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(8)

7-Fluoro-1,2,3,4-tetrahydroquinoline hydrochloride (165 mg, 0.88 mmol)and N¹⁻,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(8) (70 mg, 23% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.31 (dd, J=5.0,2.9 Hz, 1H) 7.09 (dd, J=2.9, 1.3 Hz, 1H) 7.06-7.01 (m, 1H) 7.00-6.93 (m,2H) 6.69 (ddd, J=8.3, 8.3, 2.6 Hz, 1H) 5.75-4.64 (m, 1H) 3.75-3.62 (m,4H) 3.59-3.51 (m, 1H) 2.71-2.65 (m, 2H) 2.18 (s, 6H) 1.88 (quintet,J=6.4 Hz, 2H). ESI-MS (m/z): 348 [M+H]⁺.

(b)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(8a)

N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(8) (52 mg, 0.15mmol) was treated with 2M HCl/diethyl ether in diethylether using the procedure described for compound (1a) toN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide(8a) (45 mg, 78% yield). 400 MHz ¹H-NMR (DMSO-d₆, ppm): 10.15 (s, 1H)7.88 (s, 1H) 7.71 (dd, J=4.8, 2.9 Hz, 1H) 7.36 (d, J=4.8 Hz, 1H) 7.30(dd, J=12.3, 2.6 Hz, 1H) 7.25-7.17 (m, 1H) 7.13-7.06 (m, 1H) 6.74 (ddd,J=8.4, 8.4, 2.7 Hz, 1H) 4.74 (s, 1H) 4.02-3.86 (m, 1H) 3.65-3.48 (m, 3H)2.80-2.70 (m, 3H) 2.69-2.59 (m, 5H) 1.84-1.75 (m, 2H). ESI-MS (m/z):348[M+H]⁺.

Example 13N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide(9) and corresponding hydrochloride salt (9a)

(a)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide(9)

1,2,3,4-Tetrahydroquinoline (132 μL, 1.06 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-3,4-dihydroquinoline-1(2H)-carboxamide(9) as an orange oil (126 mg, 36% yield). 400 MHz ¹H-NMR (CDCl₃, ppm):7.31 (dd, J=5.0, 2.9 Hz, 1H) 7.11 (d, J=7.0 Hz, 1H) 7.09-7.05 (m, 1H)7.04 (dd, J=7.0, 1.8 Hz, 1H) 7.01-6.95 (m, 3H) 5.57 (s, 1H) 3.82-3.61(m, 4H) 3.54-3.45 (m, 1H), 2.76-2.68 (m, 2H), 2.17 (s, 6H), 1.94-1.86(m, 2H). ESI-MS (m/z): 330 [M+H]⁺.

(b)N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamidehydrochloride (9a)

N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide(9) (120 mg, 0.36 mmol) was treated with 2M HCl/diethyl ether in diethylether using procedure described for compound (1a) to produceN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-3,4-dihydroquinoline-1(2H)-carboxamidehydrochloride (9a) (120 mg, 90% yield). 400 MHz ¹H-NMR (CD₃OD, ppm):7.79 (dd, J=2.9, 1.3 Hz, 1H) 7.67 (dd, J=5.0, 2.9 Hz, 1H) 7.30 (dd,J=5.0, 1.3 Hz 1H) 7.16-7.12 (m, 1H) 7.12-7.05 (m, 2H) 7.05-7.00 (m, 1H)4.74 (t, J=7.1 Hz, 1H) 4.09 (dd, J=14.5, 7.6 Hz, 1H) 3.72- 3.55 (m, 3H)2.83 (s, 6H) 2.72 (t, J=6.5 Hz, 2H) 1.91 (quintet, J=6.5 Hz, 2H). ESI-MS(m/z): 330 [M+H]+.

Example 141-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea (10) and corresponding hydrochloride salt (10a)

(a)[1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(10)

1,2,3,4-Tetrahydronaphthalen-2-amine (173 mg, 1.17 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using procedure described for compound (1) to afford[1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(10) (135 mg, 33% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.30 (dd, J=5.0,2.9 Hz, 1H) 7.16-7.03 (m, 5H) 7.00-6.95 (m, 1H) 4.90-4.81 (m, 1H)4.77-4.62 (m, 1H) 4.15-4.01 (m, 1H) 3.67 (dd, J=8.8, 5.6 Hz, 1H)3.62-3.52 (m, 1H) 3.48-3.39 (m, 1H) 3.12 (dd, J=16.4, 5.6 Hz, 1H)2.96-2.80 (m, 2H) 2.62 (dd, J=16.4, 7.7 Hz, 1H) 2.14 (s, 6H) 2.10-2.00(m, 1H) 1.83-1.70 (m, 1H). ESI-MS (m/z): 344 [M+H]⁺.

(b)[1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)ureahydrochloride (10a)

[1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(10) (120 mg, 0.35 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH using the procedure described for compound (1a) toproduce[1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)ureahydrochloride (10a) (105 mg, 79% yield). 400 MHz ¹H-NMR (CD₃OD, ppm):7.77 (dd, J=2.9, 1.3 Hz, 1H) 7.65 (dd, J=5.1, 2.9 Hz, 1H) 7.29 (dd,J=5.1, 1.3 Hz, 1H) 7.09-7.00 (m, 4H) 4.68-4.62 (m, 1H) 4.06-3.92 (m, 2H)3.66-3.58 (m, 1H) 3.04 (dd, J=16.2, 5.1 Hz, 1H) 2.96-2.82 (m, 6H) 2.73(s, 3H) 2.64 (dd, J=16.2, 8.6 Hz, 1H) 2.09-1.98 (m, 1H) 1.78-1.66 (m,1H). ESI-MS (m/z): 344 [M+H]⁺; melting point: 151-153° C.

Example 151-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(11) and corresponding hydrochloride salt (11a)

(a)1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(11)

1,2,3,4-Tetrahydronaphthalen-1-amine (173 mg, 0.94 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to afford1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(11) (155 mg, 48% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.36-7.31 (m, 1H)7.30 (dd, J=5.0, 2.9 Hz, 1H) 7.18-7.12 (m, 2H) 7.10-7.04 (m, 2H) 6.97(dd, J=5.0, 1.3 Hz, 1H) 5.00-4.91 (m, 1H) 4.91-4.77 (m, 1H) 3.71-3.64(m, 1H) 3.63-3.54 (m, 1H) 3.49-3.40 (m, 1H) 2.85-2.67 (m, 2H) 2.13 (s,3H) 2.12 (s, 3H) 2.07-1.94 (m, 1H) 1.88-1.67 (m, 4H). ESI-MS (m/z): 344[M+H]⁺.

(b)1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)ureahydrochloride (11a)

1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(11) (141 mg, 0.41 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH using the procedure described for compound (1) toproduce1-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-3-(1,2,3,4-tetrahydronaphthalen-1-yl)ureahydrochloride (11a) (115 mg, 74% yield). 400 MHz ¹H NMR (CD₃OD, ppm):7.80-7.77 (m, 1H) 7.68-7.64 (m, 1H) 7.32-3.29 (m, 1H) 7.24-7.20 (m, 1H)7.15-7.09 (m, 2H) 7.09-7.04 (m, 1H) 5.92-4.82 (m, 2H) 4.69 (ddd, J=10.2,7.5, 6.2 Hz, 1H) 4.05 (ddd, J=14.8, 7.5, 1.3 Hz, 1H) 3.67 (ddd, J=14.8,8.3, 6.2 Hz, 1H) 3.01-2.65 (m, 8H) 2.07-1.95 (m, 1H) 1.94-1.70 (m, 3H).ESI-MS (m/z): 344 [M+H]⁺; melting point: 179-181° C.

Example 16N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamidehydrochloride (12) and corresponding hydrochloride salt (12a)

(a)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamide(12)

5-Methylisoindoline (140 mg, 1.06 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using the procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-methylisoindoline-2-carboxamide(12) (140 mg, 40% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.32 (dd, J=5.0,2.9 Hz, 1H) 7.16-7.13 (m, 1H) 7.12 (dd, J=2.9, 1.3 Hz, 1H) 7.10-7.07 (m,2H) 7.02 (dd, J=5.0, 1.3 Hz, 1H) 5.01-4.88 (m, 1H) 4.70-4.54 (m, 4H)3.77-3.70 (m, 1H) (dd, J=8.5, 3.7 Hz, 1H) 3.62-3.50 (m, 1H) 2.36 (s, 3H)2.22 (s, 6H). ESI-MS (m/z): 352 [M+H]⁺.

(b)N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamidehydrochloride (12a)

N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl-5-methylisoindoline-2-carboxamide(12) (120 mg, 0.36 mmol) was treated with 2M HCl/diethyl ether indiethyl ether using the procedure described for compound (1) to produceN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamidehydrochloride (12a) (110 mg, 82% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.81 (dd, J=2.9, 1.4 Hz, 1H) 7.66 (dd, J=5.0, 2.9 Hz, 1H) 7.35-7.30 (m,1H) 7.22-7.16 (m, 1H) 7.16-7.09 (m, 2H) 4.75 (dd, J=9.0, 4.7 Hz, 1H)4.71-4.58 (m, 4H) 4.12 (dd, J=15.1, 9.0 Hz, 1H) 3.64 (dd, J=15.1, 4.7Hz, 1H) 2.82 (s, 6H) 2.35 (s, 3H). ESI-MS (m/z): 330[M+H]⁺; meltingpoint: 200-202° C. (dec.).

Example 173-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(13) and corresponding hydrochloride salt (13a)

(a)3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(13)

N-Methyl-1,2,3,4-tetrahydronaphthalen-1-amine (150 mg, 0.93 mmol) andN¹,N¹-dimethyl-1-(thiophen-3-yl)ethane-1,2-diamine were reacted inCH₂Cl₂ using procedure described for compound (1) to afford3-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(13) (64 mg, 19% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.31 (dd, J=4.9,2.9 Hz, 1H) 7.16-7.04 (m, 5H), 7.03-6.98 (m, 1H) 5.58-5.38 (m, 1H)5.10-4.92 (m, 1H) 3.74-3.62 (m, 2H) 3.61-3.49 (m, 1H) 2.84-2.71 (m, 2H)2.60-2.50 (m, 3H) 2.23-2.13 (m, 6H) 2.09-1.92 (m, 2H) 1.87-1.49 (m, 2H).ESI-MS (m/z): 358 [M+H]⁺.

(b)3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)ureahydrochloride (13a)

3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea(13) (60 mg, 0.17 mmol) was treated with 2M HCl/diethyl ether in diethylether using procedure described for compound (1) to produce3-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)ureahydrochloride (13a) (55 mg, 83% yield). 400 MHz ¹H-NMR (CD₃OD, ppm):7.83-7.75 (m, 1H) 7.71-7.64 (m, 1H) 7.31 (dd, J=5.0, 1.2 Hz, 1H)7.17-7.05 (m, 3H) 7.03-6.91 (m, 1H) 5.46 (s, 1H) 4.75 (ddd, J=14.3, 7.8,5.6 Hz, 1H) 4.16-4.01 (m, 1H) 3.69 (ddd, J=14.7, 5.6, 3.5 Hz, 1H)2.98-2.72 (m, 8H) 2.56-2.53 (m, 3H) 2.07-1.93 (m, 2H) 1.88- 1.71 (m,2H). ESI-MS (m/z): 358 [M+H]⁺; melting point: 188-190° C.

Example 18N-(2-(2-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)isoindoline-2-carboxamide(14) and corresponding hydrochloride salt (14a)

(a)N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)isoindoline-2-carboxamide(14)

Isoindoline (99 mg, 0.83 mmol) and1-(2-chloro-4-fluorophenyl)-N¹,N¹-dimethylethane-1,2-diamine werereacted in CH₂Cl₂ using procedure described for compound (1) to affordN-(2-(2-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)isoindoline-2-carboxamide(14) (185 mg, 62% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.45 (dd, J=8.6,6.2 Hz, 1H) 7.31-7.23 (m, 3H) 7.14 (dd, J=8.6, 2.6 Hz, 1H) 7.05-6.97 (m,1H) 4.71-4.54 (m, 5H) 4.04 (t, J=6.3 Hz, 1H) 3.82-3.72 (m, 1H) 3.49(ddd, J=13.3, 6.3, 5.2 Hz, 1H) 2.26 (s, 6H). ESI-MS (m/z): 362, 364[M+H]⁺.

(b)N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)isoindoline-2-carboxamidehydrochloride (14a)

N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)isoindoline-2-carboxamide(14) (170 mg, 0.47 mmol) was treated with 2M HCl/diethyl ether indiethyl ether using procedure described for compound (1) to produceN-(2-(2-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-isoindoline-2-carboxamide hydrochloride (14b) (160 mg, 86%yield). 300 MHz ¹H-NMR (CD₃OD, ppm): 7.74 (dd, J=8.5, 5.8 Hz, 1H) 7.48(dd, J=8.5, 2.7 Hz, 1H) 7.37-7.25 (m, 5H) 5.17-5.05 (m, 1H) 4.73-4.54(m, 4H) 4.10 (dd, J=14.8, 6.8 Hz, 1H) 3.73 (dd, J=14.8, 5.9 Hz, 1H)3.11-2.73 (m, 6H). ESI-MS (m/z): 362, 364 [M+H]⁺; melting point:147-149° C.

Example 19N-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl)isoindoline-2-carboxamide(15) and corresponding hydrochloride salt (15a)

(a)N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)isoindoline-2-carboxamide(15)

Isoindoline (123 mg, 1.03 mmol) and1-(4-methoxyphenyl)-N¹,N¹-dimethylethane-1,2-diamine were reacted inCH₂Cl₂ using procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl)isoindoline-2-carboxamide(15) (190 mg, 54% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.30-7.22 (m, 4H)7.21-7.14 (m, 2H) 6.92-6.85 (m, 2H) 4.78-4.55 (m, 5H) 3.85-3.74 (m, 1H)3.81 (s, 3H) 3.51-3.37 (m, 2H) 2.20 (s, 6H). ESI-MS (m/z): 340 [M+H]⁺.

(b)N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)isoindoline-2-carboxamidehydrochloride (15a)

N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)isoindoline-2-carboxamide(15) (165 mg, 0.49 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH (25 mL/2 mL) using procedure described for compound(1) to produceN-(2-(dimethylamino)-2-(4-methoxyphenyl)-ethyl)isoindoline-2-carboxamidehydrochloride (15a) (148 mg, 81% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.51-7.42 (m, 2H) 7.36-7.23 (m, 4H) 7.11-7.03 (m, 2H) 4.77-4.59 (m, 4H)4.55 (dd, J=8.7, 5.0 Hz, 1H) 4.16 (dd, J=15.0, 8.7 Hz, 1H) 3.83 (s, 3H)3.66 (dd, J=15.0, 5.0 Hz, 1H) 2.81 (s, 6H). ESI-MS (m/z): 340 [M+H]⁺;melting point: 149-151° C. (dec.).

Example 20N-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl-5-fluoroisoindoline-2-carboxamide(16) and corresponding hydrochloride salt (16a)

(a)N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamide(16)

5-Fluoroisoindoline hydrochloride (115 mg, 0.59 mmol) and1-(4-methoxyphenyl)-N¹,N¹-dimethylethane-1,2-diamine were reacted inCH₂Cl₂ using procedure described for compound (1) to affordN-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamide(16) (120 mg, 81% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.23-7.14 (m, 3H)7.01-6.92 (m, 2H) 6.92-6.86 (m, 2H) 4.80-4.71 (m, 1H) 4.68-4.50 (m, 4H)3.84-3.72 (m, 1H) 3.81 (s, 3H) 3.51-3.37 (m, 2H) 2.20 (s, 6H). ESI-MS(m/z): 358 [M+H]⁺.

(b)N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (16a)

N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl-5-fluoroisoindoline-2-carboxamide(16) (115 mg, 0.32 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH (25 mL/0.5 mL) using procedure described for compound(1) to produceN-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (16a) (104 mg, 82% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.50-7.42 (m, 2H) 7.31 (dd, J=8.3, 5.0 Hz, 1H) 7.12-6.99 (m, 4H)4.77-4.57 (m, 4H) 4.53 (dd, J=8.6, 5.1 Hz, 1H) 4.14 (dd, J=15.0, 8.6 Hz,1H) 3.83 (s, 3H) 3.65 (dd, J=15.0, 5.1 Hz, 1H) 2.87 (s, 3H) 2.75 (s,3H). ESI-MS (m/z): 358 [M+H]⁺; melting point: 145-149° C. (dec.).

Example 21N-(2-(2-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamide(17) and corresponding hydrochloride salt (17a)

(a)N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamide(17)

5-Fluoroisoindoline hydrochloride (71 mg, 0.41 mmol) and1-(2-chloro-4-fluorophenyl)-N¹,N¹-dimethylethane-1,2-diamine werereacted in CH₂Cl₂ using procedure described for compound (1) to affordN-(2-(2-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamide(17) (135 mg, 87% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.44 (dd, J=8.7,6.3 Hz, 1H) 7.20 (dd, J=8.0, 5.0 Hz, 1H) 7.14 (dd, J=8.7, 2.6 Hz, 1H)7.06-6.92 (m, 3H) 4.70-4.51 (m, 5H) 4.05 (t, J=6.3 Hz, 1H) 3.80-3.70 (m,1H) 3.54-3.43 (m, 1H) 2.26 (s, 6H). ESI-MS (m/z): 380, 382 [M+H]⁺.

(b)N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (17a)

N-(2-(2-Chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamide(17) (120 mg, 0.34 mmol) was treated with 2M HCl/diethyl ether indiethyl ether using procedure described for compound (1) to produceN-(2-(2-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (17 a) . 300 MHz ¹H-NMR (CD₃OD, ppm): 7.75 (dd, J=8.5, 5.8Hz, 1H) 7.49 (dd, J=8.5, 2.7 Hz, 1H) 7.37-7.25 (m, 2H) 7.10-6.98 (m, 2H)5.17-5.05 (m, 1H) 4.73-4.54 (m, 4H) 4.10 (dd, J=14.8, 6.8 Hz, 1H) 3.74(dd, J=14.8, 5.9 Hz, 1H) 3.16-2.58 (m, 6H). ESI-MS (m/z): 380, 382[M+H]⁺; melting point: 173-174° C. (dec.).

Example 22 N-(2-(dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide(18) and corresponding hydrochloride salt (18a)

(a) N-(2-(Dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide (18)

Isoindoline (100 mg, 0.84 mmol) andN¹,N¹-dimethyl-1-phenylethane-1,2-diamine were reacted in CH₂Cl₂ usingprocedure described for compound (1) to affordN-(2-(dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide (18) (120mg, 46% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.40-7.22 (m, 9H) 4.80-4.70(m, 1H) 4.70-4.56 (m, 4H) 3.89-3.77 (m, 1H) 3.56-3.42 (m, 3H) 2.24 (s,6H). ESI-MS (m/z): 310 [M+H]⁺.

(b) N-(2-(Dimethylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (18a)

N-(2-(Dimethylamino)-2-phenylethyl)isoindoline-2-carboxamide (18) (109mg, 0.35 mmol) was treated with 2M HCl/diethyl ether in diethyl etherusing procedure described for compound (1) to produceN-(2-(dimethylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (18a) (100 mg, 82% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.62-7.47 (m, 5H) 7.38-7.22 (m, 4H) 4.77-4.61 (m, 4H) 4.57 (dd, J=8.1,5.1 Hz, 1H) 4.16 (dd, J=15.0, 8.1 Hz, 1H) 3.71 (dd, J=15.0, 5.1 Hz, 1H)2.86 (s, 6H). ESI-MS (m/z): 310 [M+H]⁺; melting point: 107-108° C.

Example 231-(2-(dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(19) and corresponding hydrochloride salt (19a)

(a)1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(19)

1,2,3,4-Tetrahydronaphthalen-2-amine (80 mg, 0.54 mmol) andN¹,N¹-dimethyl-1-phenylethane-1,2-diamine were reacted in CH₂Cl₂ usingprocedure described for compound (1) to afford1-(2-(dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(19) (155 mg, 85% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.38-7.28 (m, 3H)7.23-7.17 (m, 2H) 7.14-7.01 (m, 4H) 4.76-4.60 (m, 2H) 4.11-3.96 (m, 1H)3.77-3.63 (m, 1H) 3.50-3.34 (m, 2H) 3.06-3.02 (m, 1H) 2.91-2.80 (m, 2H)2.60 (dd, J=16.3, 7.9 Hz, 1H) 2.16 (s, 6H) 2.08-1.95 (m, 1H) 1.82-1.65(m, 1H). ESI-MS (m/z): 338 [M+H]⁺.

(b)1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)ureahydrochloride (19a)

1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea(19) (150 mg, 0.44 mmol) was treated with 2M HCl/diethyl ether indiethyl ether using procedure described for compound (1) to produce1-(2-(dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydro-naphthalen-2-yl)ureahydrochloride (19a) (120 mg, 85% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.59-7.43 (m, 5H) 7.13-6.96 (m, 4H) 4.48 (td, J=6.6, 2.1 Hz, 1H)4.10-3.90 (m, 2H) 3.69 (ddd, J=14.8, 6.6, 3.6 Hz, 1H) 3.02 (dd, J=16.3,5.2 Hz, 1H) 3.02-2.59 (m, 6H) 2.97-2.67 (m, 2H) 2.62 (dd, J=16.3, 8.5Hz, 1H) 2.08-1.95 (m, 1H) 1.79-1.62 (m, 1H).

ESI-MS (m/z): 338 [M+H]⁺; melting point: 160-161° C.

Example 24N-(2-(dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamide(20) and corresponding hydrochloride salt (20a)

(a)N-(2-(Dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamide(20)

A mixture of N¹,N¹-dimethyl-1-phenylethane-1,2-diamine (176 mg, 1.07mmol) and N,N-diisopropylethylamine (260 μL, 1.50 mmol) in CH₂Cl₂ (10mL) was purged with argon and cooled to −70° C. A solution of4-nitrophenylchloroformate (2) (216 mg, 1.07 mmol) in CH₂Cl₂ (5 mL) wasadded and resulting solution was stirred at −70° C. for 30 min. Afterthis time, 5-fluoroisoindoline hydrochloride (130 mg, 0.75 mmol) wasadded followed by N,N-diisopropylethylamine (390 pt, 2.24 mmol), and theresulting mixture was stirred for 16 h at room temperature. A saturatedNaHCO₃ solution (10 mL) was added and the resulting suspension wasextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts werewashed with water (30 mL) and dried over solid anhydrous MgSO₄. Afterfiltration, the volatiles were removed, and the residue was purified byflash chromatography using eluent from CH₂Cl₂ to CH₂Cl₂/MeOH (10:1) togiveN-(2-(dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamide(20) as an oil (178 mg, 73% yield). 300 MHz ¹H-NMR (CDCl₃, ppm):7.40-7.30 (m, 3H) 7.30-7.24 (m, 2H) 7.19 (dd, J=8.1, 4.9 Hz, 1H)7.02-6.91 (m, 2H) 4.81-4.69 (m, 1H) 4.69-4.49 (m, 4H) 3.91-3.72 (m, 1H)3.56-3.41 (m, 2H) 2.23 (s, 6H). ESI-MS (m/z): 328 [M+H]⁺.

(b)N-(2-(Dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (20a)

N-(2-(Dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamide(20) (174 mg, 0.53 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH using procedure described for compound (1) to produceN-(2-(dimethylamino)-2-phenylethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (20a) (185 mg, 96% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.54 (s, 5H) 7.31 (dd, J=8.2, 5.2 Hz, 1H) 7.15-6.96 (m, 2H) 4.71-4.61(m, 4H) 4.58 (dd, J=8.1, 5.1 Hz, 1H), 4.15 (dd, J=15.0, 8.1 Hz, 1H) 3.71(dd, J=15.0, 5.1 Hz, 1H) 2.85 (s, 6H). ESI-MS (m/z): 328 [M+H]⁺; meltingpoint: 148-150° C.

Example 25N-(2-(Dimethylamino)-2-(4-hydroxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamide(21) and corresponding hydrochloride salt (21a)

(a)N-(2-(Dimethylamino)-2-(4-hydroxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamide(21)

A 1M BBr₃/CH₂Cl₂ solution (2.80 mL, 2.80 mmol) was added dropwise to thesolution ofN-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl-5-fluoroisoindoline-2-carboxamide(16) (100 mg, 0.28 mmol) in CH₂Cl₂ (3 mL) at 0° C. under an argonatmosphere. The reaction mixture was stirred at room temperature for 20h. After this time, MeOH (3 mL) was added, and the mixture was stirredfor 30 min. The volatiles were removed in vacuo, and the resultantresidue was purified by flash chromatography using gradient elution fromCH₂Cl₂ to CH₂Cl₂/MeOH (4:1) to giveN-(2-(dimethylamino)-2-(4-hydroxyphenyl)ethyl-5-fluoroisoindoline-2-carboxamide(21) (70 mg, 73% yield). 300 MHz ¹H-NMR (CD₃OD, ppm): 7.34-7.21 (m, 3H)7.10-6.97 (m, 2H) 6.90-6.82 (m, 2H) 4.72-4.48 (m, 4H) 4.17-4.06 (m, 1H)4.01 (dd, J=14.0, 7.8 Hz, 1H) 3.55 (dd, J=14.0, 5.9 Hz) 2.56 (s, 6H);ESI-MS (m/z): 344 [M+H]⁺.

(b)N-(2-(Dimethylamino)-2-(4-hydroxyphenyl)ethyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (21a)

A 2M HCl/diethyl ether solution (100 μL, 0.20 mmol) was added to thesolution ofN-(2-(dimethylamino)-2-(4-hydroxyphenyl)ethyl-5-fluoroisoindoline-2-carboxamide(21) (70 mg, 0.20 mmol) in diethyl ether/MeOH (5 mL/1.5 mL). The mixturewas stirred for 2 h at ambient temperature. The resultant precipitatewere filtered and dried over P₂O₅ in vacuo at 65° C. for 24 h to giveN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (21a) (65 mg, 84% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.40-7.26 (m, 3H) 7.14-6.97 (m, 2H) 6.97-6.84 (m, 2H) 4.77-4.58 (m, 4H)4.50 (dd, J=8.8, 5.0 Hz, 1H) 4.14 (dd, J=15.0, 8.8 Hz, 1H) 3.63 (dd,J=15.0, 5.0 Hz, 1H) 2.84 (s, 3H) 2.75 (s, 3H); ESI-MS (m/z): 344 [M+H]⁺;melting point: 180-185° C. (dec.).

Example 26N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-hydroxyisoindoline-2-carboxamidehydrobromide (22a)

A 1M BBr₃/CH₂Cl₂ solution (1.45 mL, 1.45 mmol) was added dropwise to thesolution ofN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-methoxyisoindoline-2-carboxamide(5) (50 mg, 0.14 mmol) in CH₂Cl₂ (10 mL) at 0° C. under argonatmosphere. The reaction mixture was stirred at room temperature for 24h. After this time, MeOH (10 mL) was added and the mixture was stirredfor 30 min. The volatiles were removed in vacuo, and the resultant oilyresidue was treated with CH₂Cl₂. The resultant precipitate werefiltered, washed with CH₂Cl₂, then with Et₂O, and dried to giveN-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl-5-hydroxyisoindoline-2-carboxamidehydrobromide (22a) (70 mg, 73% yield). 300 MHz ¹H-NMR (DMSO-d₆, ppm):10.2-8.6 (br s, 1H) 9.47 (s, 1H) 7.92 (dd, J=2.9, 1.2 Hz, 1H) 7.73 (dd,J=5.0, 2.9 Hz, 1H) 7.36 (dd, J=5.0, 1.2 Hz, 1H) 7.15-7.08 (m, 1H)6.80-6.67 (m, 3H) 4.76-4.66 (m, 1H) 4.60-4.43 (m, 4H) 3.90 (ddd, J=15.0,8.8, 6.2 Hz, 1H) 3.55-3.42 (m, 1H) 2.71 (d, J=4.8 Hz, 3H) 2.64 (d, J=4.8Hz, 3H); ESI-MS (m/z): 332 [M+H]⁺; melting point: 134° C. (dec.).

Example 27N-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-methoxyisoindoline-2-carboxamide(23) and N-(2-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)-5-hydroxyisoindoline-2-carboxamide hydrobromide (24a)

(a)N-(2-(dimethylamino)-2-(4-methoxyphenyl)ethyl)-5-methoxyisoindoline-2-carboxamide(23)

A mixture of 1-(4-methoxyphenyl)-N¹,N¹-dimethylethane-1,2-diamine (78mg, 0.40 mmol) and N,N-diisopropylethylamine (70 μL, 0.40 mmol) inCH₂Cl₂ (10 mL) was purged with argon and cooled to 0 C. A solution of4-nitrophenylchloroformate (81 mg, 0.40 mmol) in CH₂Cl₂ (5 mL) wasadded, and resulting solution was stirred at -70° C. for 30 min. Afterthis time, 5-methoxyisoindoline hydrochloride (50 mg, 0.27 mmol) wasadded, followed by N,N-diisopropylethylamine (93 μL, 0.54 mmol), and theresulting mixture was stirred for 16 h at room temperature. A saturatedNaHCO₃ solution (10 mL) was added, and the resulting suspension wasextracted with EtOAc (3×10 mL). The combined organic extracts werewashed with water (30 mL), then with a brine solution (20 mL) and driedover solid anhydrous Na₂SO₄. After filtration, the volatiles wereremoved and the residue was purified by flash chromatography usingeluent from CH₂Cl₂ to CH₂Cl₂/MeOH (1:1) to give N-(2-(dimethylamino)-2-(4-methoxy phenyl)ethyl)-5-methoxyisoindoline-2-carboxamide(23) (79 mg, 79% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.23-7.10 (m, 2H)6.94-6.86 (m, 2H) 6.86-6.76 (m, 3H) 4.64-4.52 (m, 4H) 3.86-3.77 (m, 1H)3.82 (s, 3H) 3.80 (s, 3H) 3.53-3.46 (m, 2H) 2.20 (s, 6H); ESI-MS (m/z):370 [M+H]⁺.

(b)N-(2-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)-5-hydroxyisoindoline-2-carboxamidehydrobromide (24a)

N-(2-(Dimethylamino)-2-(4-methoxyphenyl)ethyl-5-methoxyisoindoline-2-carboxamide(23) (75 mg, 0.20 mmol) and 1M BBr₃/CH₂Cl₂ were reacted in CH₂Cl₂ usingprocedure described for compound (22a) to obtainN-(2-(dimethylamino)-2-(4-hydroxyphenyl)ethyl)-5-hydroxyisoindoline-2-carboxamidehydrobromide (24a) (65 mg, 94% yield). 300 MHz ¹H-NMR (DMSO-d₆, ppm):10.7-8.7 (br s, 2H) 9.79 (br s, 1H) 9.52-9.30 (m, 1H) 7.41-7.27 (m, 2H)7.15-7.05 (m, 1H) 6.91-6.78 (m, 2H) 6.77-6.61 (m, 3H) 4.60-4.37 (m, 5H)3.91 (ddd, J=14.8, 8.5, 6.3 Hz, 1H) 3.47 (ddd, J=14.8, 4.9, 4.9 Hz, 1H)2.69 (d, J=4.8 Hz, 3H) 2.59 (d, J=4.8 Hz, 3H); ESI-MS (m/z): 342 [M+H]⁺;melting point: 185° C. (dec.).

Example 28(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-R) and(R)—N-(3-(dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (30a-R)

(a) (R)-2-Methyl-N-(thiophen-3-ylmethylene)propane-2-sulfinamide (25-R)

A mixture of thiophene-3-carboxaldehyde (1.50 g, 13.38 mmol),(R)-(+)-2-methyl-2-propanesulfinamide (1.62 g, 13.38 mmol), pyrrolidine(111 μL, 1.34 mmol), and molecular sieves (3 Å) (0.1 g) in CH₂Cl₂ (18mL) was heated at 50° C. for 10 h in a closed vial. After cooling, thevolatiles were removed in vacuo, and the resultant residue was purifiedby flash chromatography using CH₂Cl₂ as an eluent to give(R)-2-methyl-N-(thiophen-3-ylmethylene) propane-2-sulfinamide (25-R)(2.68 g, 93% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 8.58 (s, 1H) 7.86 (dd,J=2.9, 1.1 Hz, 1H) 7.58 (dd, J=5.1, 1.1 Hz, 1H) 7.37 (ddd, J=5.1, 2.9,0.6 Hz, 1H) 1.25 (s, 9H); ESI-MS (m/z): 216 [M+H]⁺.

(b)(R)—N—((R)-2-Cyano-1-(thiophen-3-yl)ethyl)-2-methylpropane-2-sulfinamide(26-R,R) and(R)—N—((S)-2-cyano-1-(thiophen-3-yl)ethyl)-2-methylpropane-2-sulfinamide(26-R,S)

An oven dried flask with N,N-diisopropylamine (1.16 mL, 8.27 mmol) inTHF (10 mL) was purged with argon and cooled to −78° C. (Dry Ice/acetonebath). A solution of n-butyllithium in hexane (3.75 mL, 2.2 M) wasadded, and the mixture was stirred at ambient temperature for 20 min.The reaction mixture was cooled to −78° C. and a solution ofacetonitrile (0.43 mL, 8.26 mmol) in THF (5 mL) was added. Afterstirring at −78° C. for 10 min. a solution of(R)-2-methyl-N-(thiophen-3-ylmethylene)propane-2-sulfinamide (25-R)(1.78 g, 8.26 mmol) in THF (10 mL) was added dropwise. The reactionmixture was stirred at −78° C. for 20 min, after which time a saturatedaqueous NH₄Cl (30 mL) was added and the mixture was allowed to reachroom temperature. The mixture was extracted with EtOAc (3×20 mL). Thecombined organic extracts were washed with water (50 mL), then with abrine solution (50 mL) and dried over solid anhydrous Na₂SO₄. Afterfiltration, the volatiles were removed in vacuo and the resultantresidue was purified by flash chromatography using eluent gradient fromCH₂Cl₂ to CH₂Cl₂/Et₂O (1:4) to give(R)—N—((R)-2-cyano-1-(thiophen-3-yl)ethyl)-2-methylpropane-2-sulfinamide(26-R,R) (0.88 g, 41% yield) and(R)—N—((S)-2-cyano-1-(thiophen-3-yl)ethyl-2-methylpropane-2-sulfinamide(26-R,S) (1.00 g, 47% yield).

-   (26-R,R): 300 MHz ¹H-NMR (CDCl₃, ppm): 7.42-7.33 (m, 2H) 7.21-7.14    (m, 1H) 4.89-4.81 (m, 1H) 3.63 (d, J=4.0 Hz, 1H) 3.01 (dd, J=16.8,    5.8 Hz, 1H) 2.85 (dd, J=16.8, 5.2 Hz, 1H) 1.29 (s, 9H); ESI-MS    (m/z): 257 [M+H]⁺.-   (26-R,S): 300 MHz ¹H-NMR (CDCl₃, ppm): 7.41-7.30 (m, 2H) 7.10 (dd,    J=4.9, 1.5 Hz, 1H) 4.87-4.78 (m, 1H) 3.76 (d, J=6.5 Hz, 1H) 3.03    (dd, J=16.8, 5.8 Hz, 1H) 2.98 (dd, J=16.8, 5.4 Hz, 1H) 1.29 (s, 9H);    ESI-MS (m/z): 257 [M+H]⁺.

(c) (R)-3-Amino-3-(thiophen-3-yl)propanenitrile hydrogen chloride (27-R)

A 4N HCl/1,4-dioxane solution (2.1 mL, 8.40 mmol) was added to asolution of(R)—N—((R)-2-cyano-1-(thiophen-3-yl)ethyl-2-methylpropane-2-sulfinamide(26-R,R) (540 mg, 2.11 mmol) in THF (20 mL). The mixture was stirred atambient temperature for 1 h. The solvents were removed under reducedpressure. The crude product was suspended in diethyl ether (30 mL) andEtOH (0.5 mL) was added. The solvents were decanted, and the remainingprecipitate was washed with diethyl ether (2×30 mL) and dried to give(R)-3-amino-3-(thiophen-3-yl)propanenitrile hydrogen chloride (27-R)(390 mg, 98% yield). 400 MHz ¹H-NMR (DMSO-d₆, ppm): 9.02 (s, 3H) 7.81(dd, J=3.0, 1.3 Hz, 1H) 7.81 (dd, J=5.1, 3.0 Hz, 1H) 7.40 (dd, J=5.1,1.3 Hz, 1H) 4.80 (dd, J=8.6, 5.2 Hz, 1H) 3.46-3.23 (m, 2H); ESI-MS(m/z): 153 [M+H]⁺.

(d) (R)-3-(Dimethylamino)-3-(thiophen-3-yl)propanenitrile (28-R)

To a suspension of (R)-3-amino-3-(thiophen-3-yl)propanenitrile hydrogenchloride (27-R) (410 mg, 2.17 mmol) and formaldehyde solution in water(37%) (0.77 mL, 9.56 mmol) in MeCN (20 mL), solid Na(AcO)₃BH (2.30 g,10.86 mmol) was added in portions. The reaction mixture was stirred atambient temperature for 1 h, and then quenched by adding a saturatedaqueous Na₂CO₃ solution (20 mL). The resultant mixture was extractedwith CH₂Cl₂ (3×15 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated in vacuo. Product purified by flashchromatography using eluent gradient from CH₂Cl₂ to CH₂Cl₂/Et₂O (1:4) togive (R)-3-(dimethylamino)-3-(thiophen-3-yl)propanenitrile (28-R) (370mg, 95% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.34 (dd, J=5.0, 2.9 Hz,1H) 7.20-7.15 (m, 1H) 7.06 (dd, J=5.0, 1.4 Hz, 1H) 3.87-3.80 (m, 1H)2.84 (dd, J=16.7, 6.3 Hz, 1H) 2.76 (dd, J=16.7, 7.3 Hz, 1H) 2.23 (s,6H). ESI-MS (m/z): 181 [M+H]⁺.

(e) (R)—N¹,N¹-Dimethyl-1-(thiophen-3-yl)propane-1,3-diamine (29-R)

A solution of (R)-3-(dimethylamino)-3-(thiophen-3-yl)propanenitrile(28-R) (370 mg, 2.05 mmol) in diethyl ether (10 mL) was added dropwise(1 mL/min) to a suspension of lithium aluminum hydride (230 mg, 6.16mmol) in diethyl ether (20 mL) at 0° C. under an argon atmosphere. Themixture was heated at reflux for 90 min, then cooled in an ice coldwater bath and lastly quenched by addition of water (370 μL), 2N aqueousNaOH (370 μL) and water (1.11 mL). The resultant white precipitate wasfiltered through a Celite plug, and the plug was washed with diethylether (50 mL). The filtrate was evaporated to give(R)—N¹,N¹-dimethyl-1-(thiophen-3-yl)propane-1,3-diamine (29-R) (375 mg,99% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.30-7.26 (m, 1H) 7.07-7.01 (m,1H) 6.99 (dd, J=4.9, 1.3 Hz, 1H) 3.56 (dd, J=8.8, 6.0 Hz, 1H) 2.66-2.58(m, 2H) 2.16 (s, 6H) 2.09-1.93 (m, 1H) 1.92-1.78 (m, 1H); ESI-MS (m/z):185 [M+H]⁺.

(f)(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-R)

4-Fluoroisoindoline hydrochloride (80 mg, 0.46 mmol) and(R)—N¹,N¹-dimethyl-1-(thiophen-3-yl)propane-1,3-diamine (0.12 g, 0.66mmol) were reacted in CH₂Cl₂ using procedure described for compound (3)to afford(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-R) (135 mg, 87% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.31 (dd,J=4.9, 2.9 Hz, 1H) 7.20 (dd, J=8.1, 5.0 Hz, 1H) 7.10 (dd, J=2.9, 1.1 Hz,1H) 7.01 (dd, J=4.9, 1.1 Hz, 1H) 7.00-6.93 (m, 2H) 5.96 (t, J=4.7 Hz,1H) 4.66-4.55 (m, 4H) 3.80-3.67 (m, 1H) 3.54-3.41 (m, 1H) 3.38-3.26 (m,1H) 2.24 (s, 6H) 2.23-2.14 (m, 1H) 2.03-1.89 (m, 1H). ESI-MS (m/z): 348[M+H]⁺. [a_(D) ²⁰]: -7.2 (1.35, acetone).

(e)(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (30a-R)

A 2M HCl/diethyl ether solution (194 μL, 0.39 mmol) was added to thesolution of(R)—N-(3-(dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-R) (135 mg, 0.39 mmol) in diethyl ether/MeOH (25 mL/1 mL). Themixture was stirred at ambient temperature for 2 h. The solvents wereremoved via decantation. The resultant precipitate was washed withdiethyl ether (2×30 mL) and dried over P₂O₅ in vacuo at 65° C. for 24 hto give(R)—N-(3-(dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (30a-R) (138 mg, 93% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.86-7.72 (m, 1H) 7.60 (dd, J=5.1, 2.9 Hz, 1H) 7.38-7.24 (m, 2H)7.11-6.97 (m, 2H) 4.72-4.47 (m, 5H) 3.40-3.11 (m, 2H) 2.77 (s, 3H) 2.73(s, 3H) 2.51-2.23 (m, 2H); ESI-MS (m/z): 348 [M+H]⁺.

Example 29(S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-S) and(S)—N-(3-(dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (30a-S) (a) (S)-3-Amino-3-(thiophen-3-yl)propanenitrilehydrochloride (27-S)

(R)—N—((S)-2-Cyano-1-(thiophen-3-yl)ethyl-2-methylpropane-2-sulfinamide(26-R,S) (650 mg, 2.53 mmol) and 4N HCl/1,4-dioxane (2.1 mL, 8.42 mmol)were reacted in THF using procedure described for compound (27-R) toafford the desired compound (27-S) (470 mg) which was used in the nextstep without purification.

(b) (S)-3-(Dimethylamino)-3-(thiophen-3-yl)propanenitrile (28-S)

(S)-3-Amino-3-(thiophen-3-yl)propanenitrile hydrochloride (27-S) (470mg, 2.49 mmol) and formaldehyde solution in water (37%) (0.89 mL, 10.96mmol) were reacted in MeCN using procedure described for compound (28-R)to afford the desired compound (28-S) (185 mg, 38% yield in 2 steps from(26-R,S). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.34 (dd, J=5.0, 2.9 Hz, 1H)7.20-7.15 (m, 1H) 7.06 (dd, J=5.0, 1.3 Hz, 1H) 3.87-3.79 (m, 1H) 2.84(dd, J=16.7, 6.3 Hz, 1H) 2.76 (dd, J=16.7, 7.3 Hz, 1H) 2.23 (s, 6H);ESI-MS (m/z): 181 [M+H]⁺.

(c) (S)-N¹,N¹-Dimethyl-1-(thiophen-3-yl)propane-1,3-diamine (29-S)

(S)-3-(Dimethylamino)-3-(thiophen-3-yl)propanenitrile 23-S (220 mg, 1.22mmol) and lithium aluminium hydride were reacted in diethyl ether usingprocedure described for compound (28-R) to afford the desired compound(28-S) (185 mg, 82% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.30-7.26 (m,1H) 7.04-7.01 (m, 1H) 6.98 (dd, J=5.0, 1.3 Hz, 1H) 3.56 (dd, J=8.8, 6.0Hz, 1H) 2.66-2.58 (m, 2H) 2.16 (s, 6H) 2.09-1.93 (m, 1H) 1.92-1.78 (m,1H);

ESI-MS (m/z): 185 [M+H]⁺.

(d)(S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-S)

4-Fluoroisoindoline hydrochloride (82 mg, 0.47 mmol) and(S)-N¹,N¹-dimethyl-1-(thiophen-3-yl)propane-1,3-diamine were reacted inCH₂Cl₂ using procedure described for compound (3) to afford the desiredcompound (30-S) (135 mg, 82% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.30(dd, J=4.9, 2.9 Hz, 1H) 7.20 (dd, J=8.1, 5.0 Hz, 1H) 7.10 (dd, J=2.9,1.1 Hz, 1H) 7.00 (dd, J=4.9, 1.1 Hz, 1H) 7.00-6.93 (m, 2H) 5.96 (t,J=4.7 Hz, 1H) 4.66-4.55 (m, 4H) 3.77-3.67 (m, 1H) 3.55-3.43 (m, 1H)3.38-3.25 (m, 1H) 2.24 (s, 6H) 2.23-2.14 (m, 1H) 2.03-1.89 (m, 1H);ESI-MS (m/z): 348 [M+H]⁺.

(e)(S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (26-S)

(S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide(30-S) (130 mg, 0.37 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH (25 mL/2 mL) using procedure described for compound(25-R) to produce (S)—N-(3-(dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamidehydrochloride (30a-S) (131 mg, 91% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.79-7.72 (m, 1H) 7.61 (dd, J=5.0, 2.9 Hz, 1H) 7.35-7.25 (m, 2H)7.11-7.00 (m, 2H) 4.67-4.51 (m, 5H) 3.40-3.17 (m, 2H) 2.75 (s, 6H)2.50-2.21 (m, 2H); ESI-MS (m/z): 348 [M+H]⁺.

Example 30 tert-Butyl(2-(5-fluoroisoindoline-2-carboxamido)-1-(thiophen-3-yl)ethyl(methyl)carbamate(34)

(a) 2-(Methylamino)-2-(thiophen-3-yl)acetonitrile (31)

A methylamine solution (40%, aqueous) (4.62 mL, 53.50 mmol) was added tosolution of thiophene-3-carboxaldehyde (3.00 g, 26.75 mmol) in methanol(30 mL) and reaction mixture was stirred for 1 h at room temperature.After this time, TMSCN (5.35 mL, 40.132 mmol) was added and stirring wascontinued for 16 h at room temperature. A saturated aqueous NH₄C1solution (7 mL) was added, and the resulting suspension was extractedwith CH₂Cl₂ (3×20 mL). The combined organic extracts were washed withwater (30 mL) and dried over solid anhydrous MgSO₄. After filtration,the volatiles were removed to give2-(methylamino)-2-(thiophen-3-yl)acetonitrile (31) (3.78 g, 93% yield),which was used in the next step without purification. 300 MHz ¹H-NMR(CDCl₃, ppm): 7.48-7.44 (m, 1H) 7.37 (dd, J=5.0, 3.0 Hz, 1H) 7.17 (dd,J=5.0, 1.4 Hz, 1H), 4.80 (s, 1H), 2.58 (s, 3H); ESI-MS (m/z): 153[M+H]⁺.

(b) tert-Butyl (cyano(thiophen-3-yl)methyl)(methyl)carbamate (32)

Di-tert-butyl decarbonate (Boc₂O) (4.75 mL, 20.67 mmol) in methanol (10mL) was added dropwise to the solution of2-(methylamino)-2-(thiophen-3-yl)acetonitrile (31) (2.42 g, 15.90 mmol)and triethylamine (4.43 mL, 31.80 mmol) in methanol (25 mL). Thereaction mixture was stirred for 16 h at room temperature. After(rotary) evaporation, the residue was dissolved in CH₂Cl₂ (50 mL),washed with a 1N HCl solution (30 mL), then with water (30 mL) and driedover solid anhydrous MgSO₄. After filtration, the volatiles were removedto give tert-butyl (cyano(thiophen-3-yl)methyl)(methyl)carbamate (32)(3.75 g, 94% yield), which was used in the next step withoutpurification. 300 MHz ¹H-NMR (CDCl₃, ppm): 7.48-7.44 (m, 1H) 7.39 (dd,J=5.0, 3.0 Hz, 1H) 7.01 (dd, J=5.0, 1.4 Hz, 1H) 6.65-6.31 (m, 1H) 2.77(s, 3H) 1.51 (s, 9H); ESI-MS (m/z): 253 [M+H]⁺.

(c) tert-Butyl (2-amino-1-(thiophen-3-yl)ethyl)(methyl)carbamate (33)

A steel vessel was charged with a solution of tert-butyl(cyano(thiophen-3-yl)methyl) (methyl)-carbamate (32) (1.05 g, 4.16 mmol)in ethanol (20 mL) and NH₄OH (25%) (10 mL). A Raney-Nickel slurry in H₂O(700 mg) was added, and hydrogen gas was added to a pressure of 10 atm.The vessel was sealed and stirred at room temperature for 15 h. Afterdepressurization, the mixture was filtered through Celite and the Celitepad was washed with ethanol (100 mL). The filtrate was evaporated, andthe residue dissolved in CH₂Cl₂ (50 mL) and dried over solid anhydrousMgSO₄. After filtration, the volatiles were removed, and the residue waspurified by flash chromatography using eluent from CH₂Cl₂ to CH₂Cl₂/MeOH(1:1) to give tert-butyl(2-amino-1-(thiophen-3-yl)ethyl)(methyl)carbamate (33) (740 mg, 69%yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.30 (dd, J=5.0, 2.9 Hz, 1H)7.11-7.05 (m, 1H) 6.98 (dd, J=5.0, 1.4 Hz, 1H) 5.63-5.05 (m, 2H)3.84-3.63 (m, 1H) 3.27-3.15 (m, 1H), 3.15-3.02 (m, 1H) 2.62 (s, 3H) 1.50(s, 9H). ESI-MS (m/z):257 [M+H]⁺.

(d) tert-Butyl(2-(5-fluoroisoindoline-2-carboxamido)-1-(thiophen-3-yl)ethyl)(methyl)carbamate(34)

A mixture of tert-butyl(2-amino-1-(thiophen-3-yl)ethyl)(methyl)carbamate (33) (310 mg, 1.21mmol) and N,N-diisopropylethylamine (300 μL, 1.73 mmol) in CH₂Cl₂ (15mL) was purged with argon and cooled to 0° C. A solution of4-nitrophenylchloroformate (244 mg, 1.21 mmol) in CH₂Cl₂ (5 mL) wasadded, and resulting reaction mixture was stirred at −70° C. for 30 min.After this time, 5-fluoroisoindoline hydrochloride (150 mg, 0.86 mmol)was added, followed by N,N-diisopropylethylamine (450 μL, 2.60 mmol).The resulting mixture was stirred for 20 h at room temperature. Asaturated NaHCO₃ solution (10 mL) was added, and the resultingsuspension was extracted with CH₂Cl₂ (3×15 mL). The combined organicextracts were washed with water (30 mL), then with a brine solution (20mL) and dried over solid anhydrous Na₂SO₄. After filtration, thevolatiles were removed in vacuo, and the residue was purified by flashchromatography using eluent from CH₂Cl₂ to CH₂Cl₂/MeOH (1:1), thenreverse phase chromatography using eluent from H₂O/MeCN (9:1) MeCN, togive tert-butyl(2-(5-fluoroisoindoline-2-carboxamido)-1-(thiophen-3-yl)ethyl)(methyl)carbamate(34) (150 mg, 41% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.32 (dd, J=5.0,2.9 Hz, 1H) 7.24-7.14 (m, 2H) 7.05-6.91 (m, 3H) 5.63-5.41 (m, 1H)5.09-4.91 (m, 1H) 4.68 (s, 2H) 4.64 (s, 2H) 4.15-3.88 (m, 1H) 3.77-3.57(m, 1H) 2.56 (s, 3H) 1.45 (s, 9H); ESI-MS (m/z): 420 [M+H]⁺; meltingpoint: 182-184° C.

Example 315-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(35) and corresponding hydrochloride salt (35a)

(a)5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(35)

A 4M HCl/1,4-dioxane solution (343 μL, 1.37 mmol) was added totert-butyl(2-(5-fluoroisoindoline-2-carboxamido)-1-(thiophen-3-yl)ethyl)(methyl)carbamate(34) (115 mg, 0.27 mmol) in 1,4-dioxane (5 mL), and heated at 80° C. for4 h. A saturated NaHCO₃ solution (10 mL) was added, and the resultingsuspension was extracted with CH₂Cl₂ (3×10 mL). The combined organicextracts were washed with water (30 mL) and dried over solid anhydrousMgSO₄. After filtration, the volatiles were removed in vacuo, and theresidue was purified by flash chromatography using eluent from CH₂Cl₂ toCH₂Cl₂/MeOH (10:1) to give5-fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(35) (44 mg, 50% yield). 300 MHz ¹H-NMR (CDCl₃, ppm): 7.34 (dd, J=5.0,2.9 Hz, 1H) 7.24-7.16 (m, 2H) 7.08 (dd, J=5.0, 1.3 Hz, 1H) 7.02-6.92 (m,2H) 4.89-4.78 (m, 1H) 4.74-4.54 (m, 4H) 3.89 (dd, J=7.0, 5.5 Hz, 1H)3.64-3.42 (m, 2H) 2.39 (s, 3H); ESI-MS (m/z): 320 [M+H]⁺.

(b)5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (35a)

5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide(35) (44 mg, 0.14 mmol) was treated with 2M HCl/diethyl ether in diethylether/MeOH (10 mL/1 mL) using procedure described for compound (2) toproduce5-fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamidehydrochloride (35a) (45 mg, 92% yield). 300 MHz ¹H-NMR (CD₃OD, ppm):7.67 (dd, J=2.9, 1.3 Hz, 1H) 7.63 (dd, J=5.0, 2.9 Hz, 1H) 7.32 (dd,J=8.3, 5.0 Hz, 1H) 7.26 (dd, J=5.0, 1.3 Hz, 1H) 7.14- 6.98 (m, 2H)4.73-4.62 (m, 4H) 4.54 (dd, J=7.7, 4.5 Hz, 1H) 3.83 (dd, J=14.8, 7.7 Hz,1H) 3.66 (dd, J=14.8, 4.5 Hz, 1H) 2.59 (s, 3H); ESI-MS (m/z): 320[M+H]⁺.

Example 32 N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38), (−)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38-ent-A),(+)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38-ent-B), and corresponding hydrochloride salts

(a) tert-butyl (2-amino-1-phenylethyl)(methyl)carbamate (36)

tert-Butyl (2-amino-1-phenylethyl)(methyl)carbamate (36) was preparedfrom benzaldehyde using procedures described to make compound (33). 300MHz ¹H-NMR (CDCl₃, ppm): 7.40-7.18 (m, 6H) 5.24 (s, 1H) 3.30-3.08 (m,2H) 2.63 (s, 3H) 1.49 (s, 9H);

ESI-MS (m/z): 251 [M+H]⁺.

(b) tert-butyl(2-(isoindoline-2-carboxamido)-1-phenylethyl)(methyl)carbamate (37)

Isoindoline (500 mg, 4.20 mmol) and tert-butyl(2-amino-1-phenylethyl)(methyl) carbamate (36) were reacted in CH₂Cl₂using procedure described for compound (34) to obtain tert-butyl(2-(isoindoline-2-carboxamido)-1-phenylethyl)(methyl)carbamate (37)(1.49 g, 90% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.41-7.33 (m, 2H)7.33-7.29 (m, 2H) 7.29-7.23 (m, 5H) 5.62-5.41 (m, 1H) 5.19-5.00 (m, 1H)4.71 (s, 4H) 4.19-3.93 (m, 1H) 3.84-3.62 (m, 1H) 2.55 (s, 3H) 1.46 (s,9H); ESI-MS (m/z): 396 [M+H]⁺.

(c) N-(2-(methylamino)-2-phenylethyl)isoindoline-2-carboxamide (38)

Trifluoroacetic acid (1.00 mL, 13.02 mmol) was added to tert-butyl(2-(isoindoline-2-carboxamido)-1-phenylethyl)(methyl)carbamate (37)(1.49 g, 3.77 mmol) in CH₂Cl₂ (15 mL), and stirred at room temperaturefor 2 h. Volatiles were removed, saturated NaHCO₃ solution (100 mL) wasadded, and the resulting suspension was extracted with CH₂Cl₂ (3×30 mL).Combined organic extracts were washed with water (30 mL) and dried overMgSO₄. Volatiles were removed, and the residue was purified by flashchromatography using eluent from CH₂Cl₂ to CH₂Cl₂/MeOH (10:1) to giveN-(2-(methylamino)-2-phenylethyl)isoindoline-2-carboxamide (42a) (530mg, 48% yield). 400 MHz ¹H-NMR (CDCl₃, ppm): 7.59-7.53 (m, 2H) 7.47-7.34(m, 3H) 7.25-7.19 (m, 4H) 6.00-5.84 (m, 1H) 4.84-4.64 (m, 4H) 4.21 (dd,J=8.4, 4.2 Hz, 1H) 3.89-3.76 (m, 2H) 2.51 (s, 3H). ESI-MS (m/z): 296[M+H]⁺.

(−)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38-ent-A)(+)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38-ent-B)

The enantiomers were separated on chiral stationary phase chromatographyusing (Chiralpak® IC 250×30mm, 5 μm column and CH₂Cl₂/MeOH/ethanolamine(99:1:0.1) as mobile phase at 40 mL/min flow rate: Rt-(−)-enantiomer(38-ent-A)=11 min, and Rt-(+)-enantiomer (38-ent-B)=19 min.(−)-Enantiomer (38-ent-A) [α_(D) ²⁰]: −12.7 (1.00, acetone);(+)-enantiomer (38-ent-B) [α_(D) ²⁰]: +13.2 (1.02, acetone).

(d) rac-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (38a)

N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide (38) (56 mg,0.19 mmol) was treated with 2M HCl/diethyl ether in diethyl ether/MeOH(10 mL/1 mL) using procedure described for compound (2a) to produceN-(2-(methylamino)-2-phenylethyl)isoindoline-2-carboxamide hydrochloride(38a) (63 mg, 100% yield). 400 MHz ¹H-NMR (CD₃OD, ppm): 7.56-7.45 (m,5H) 7.34-7.27 (m, 4H) 4.69 (s, 4H) 4.37 (dd, J=7.8, 4.5 Hz, 1H) 3.85(dd, J=14.8, 7.8 Hz, 1H) 3.67 (dd, J=14.8, 4.5 Hz, 1H) 2.59 (s, 3H);ESI-MS (m/z): 296 [M+H]⁺.

(e) (−)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (38a-ent-A)

(−)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38-ent-A) (115 mg, 0.39 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH (12 mL/0.1 mL) using procedure described for compound(2a) to produce(−)-N-(2-(methylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (38a-ent-A) (102 mg, 79% yield). 400 MHz ¹H-NMR (CD₃OD,ppm): 7.56-7.45 (m, 5H) 7.34-7.27 (m, 4H) 4.69 (s, 4H) 4.36 (dd, J=7.8,4.5 Hz, 1H) 3.84 (dd, J=14.8, 7.8 Hz, 1H) 3.66 (dd, J=14.8, 4.5 Hz, 1H)2.58 (s, 3H);

ESI-MS (m/z): 296 [M+H]⁺.

(f) (+)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (38a-ent-B)

(+)-N-(2-(Methylamino)-2-phenylethyl)isoindoline-2-carboxamide(38-ent-B) (125 mg, 0.42 mmol) was treated with 2M HCl/diethyl ether indiethyl ether/MeOH (10 mL/0.5 mL) using procedure described for compound(2a) to produce(+)-N-(2-(methylamino)-2-phenylethyl)isoindoline-2-carboxamidehydrochloride (38a-ent-B) (109 mg, 78% yield). 400 MHz ¹H-NMR (CD₃OD,ppm): 7.54-7.43 (m, 5H) 7.34-7.27 (m, 4H) 4.69 (s, 4H) 4.30 (dd, J=7.8,4.5 Hz, 1H) 3.81 (dd, J=14.8, 7.8 Hz, 1H) 3.63 (dd, J=14.8, 4.5 Hz, 1H)2.55 (s, 3H);

ESI-MS (m/z): 296 [M+H]⁺; [α_(D) ²⁰]: +27.9 (0.66, methanol).

Other Examples

Using the synthetic methods illustrated above, the following compoundsof this invention were prepared:

Name Cpd # (free base structures shown) MP HMR MS / [α] 39a

hygroscopic powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.79 (d, J = 2.6 Hz, 1H)7.69-7.64 (m, 1H) 7.31 (dd, J = 5.1, 1.0 Hz, 1H) 7.18-7.07 (m, 3H)7.02-6.93 (m, 1H) 5.46 (s, 1H) 4.81-4.69 (m, 1H), 4.15- 4.02 (m, 1H)3.80-3.62 (m, 1H) 3.01- 2.69 (m, 8H) 2.56 (s, 1.3H) 2.54 (s, 1.7H)2.09-1.90 (m, 2H) 1.87-1.69 (m, 2H) 358 [M + H]+ 40a

foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.81-7.76 (m, 1H) 7.65 (dd, J = 5.0,2.9 Hz, 1H) 7.39-7.15 (m, 6H) 4.75- 4.62 (m, 1H) 4.06 (ddd, J = 14.9,8.7, 2.7 Hz, 1H) 3.89-3.73 (m, 1H) 3.67- 3.54 (m, 2H) 3.52-3.37 (m, 2H)3.38- 3.24 (m, 1H, overlapped with MeOD) 2.96--2.67 (m, 6H) 2.40-2.26(m, 1H) 2.15-1.97 (m, 1H) 344 [M + H]+ 41a

hygroscopic powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.82-7.75 (m, 1H) 7.65(dd, J = 4.9, 2.8 Hz, 1H) 7.36-7.18 (m, 6H) 4.76- 4.65 (m, 1H) 4.15-3.97(m, 1H) 3.89- 3.73 (m, 1H) 3.69-3.52 (m, 2H) 3.52- 3.38 (m, 2H)3.38-3.22 (m, 1H, overlapped with methanol) 2.88 (s, 3H) 2.75 (s, 3H)2.41-2.24 (m, 1H) 2.16-1.99 (m, 1H) 344 [M + H]+ 42a

foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.48-7.38 (m, 2H) 7.37-7.18 (m, 5H)7.12-7.00 (m, 2H) 4.46 (dd, J = 7.6, 5.8 Hz, 1H) 4.08 (ddd, J = 14.8,8.4, 3.0 Hz, 1H) 3.88-3.70 (m, 1H) 3.84 (s, 3H) 3.65-3.52 (m, 2H)3.51-3.37 (m, 2H) 3.37-3.25 (m, 1H, overlapped with MeOD) 2.77 (s, 6H)2.37-2.27 (m, 1H) 2.13-1.97 (m, 1H) 368 [M + H]+ 43a

foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.48-7.38 (m, 2H) 7.37-7.18 (m, 5H)7.12-7.00 (m, 2H) 4.52-4.41 (m, 1H) 4.08 (ddd, J = 14.8, 8.4, 3.1 Hz,1H) 3.88-3.70 (m, 1H) 3.84 (s, 3H) 3.67- 3.51 (m, 2H) 3.49-3.38 (m, 2H)3.37- 3.25 (m, 1H, overlapped with methanol) 2.77 (s, 6H) 2.37-2.27 (m,1H) 2.13-1.97 (m, 1H) 368 [M + H]+ 44a

159-161 300 MHz ¹H-NMR (CD₃OD, ppm) 7.82 (dd, J = 2.9, 1.3 Hz, 1H) 7.75-7.61 (m, 3H) 7.56-7.47 (m, 1H) 7.33 (dd, J = 5.0, 1.3 Hz, 1H) 4.93-4.87(m, 2H) 4.83-4.78 (m, 2H) 4.78 (dd, J = 9.0, 5.1 Hz, 1H) 4.13 (dd, J =15.1, 9.0 Hz, 1H) 3.66 (dd, J = 15.1, 5.0 Hz, 1H) 2.83 (s, 6H) 341 [M +H]+ 45a

foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.83-7.77 (m, 1H) 7.70-7.63 (m, 1H)7.32 (d, J = 5.0, 1H) 7.17-7.06 (m, 3H) 7.02-6.93 (m, 1H) 5.46 (s, 1H)4.82- 4.70 (m, 1H) 4.09 (ddd, J = 14.5, 7.6, 6.1 Hz, 1H) 3.77-3.64 (m,1H) 3.01- 2.62 (m, 8H) 2.57-2.51 (m, 3H) 2.09- 1.91 (m, 2H) 1.88-1.68(m, 2H). 358 [M + H]+ 46a

foam 400 MHz ¹H-NMR (CD₃OD, ppm) 7.33 (dd, J = 8.4, 5.0 Hz, 1H) 7.12-7.01 (m, 2H) 4.75-4.69 (m, 4H) 3.69 (s, 2H) 2.86 (s, 6H) 1.97-1.86 (m,2H) 1.85-1.55 (m, 7H) 1.38-1.26 (m, 1H). 320 [M + H]+ 47a

amorphous powder 400 MHz ¹H-NMR (CD₃OD, ppm) 7.53 (dd, J = 5.0, 2.9 Hz,1H) 7.50 (s, 1H) 7.17 (dd, J = 5.0, 1.3 Hz, 1H) 7.07-7.04 (m, 3H)7.04-7.00 (m, 1H) 4.19-4.08 (m, 1H) 3.99-3.89 (m, 1H) 3.85 (dd, J =14.1, 7.1 Hz, 1H) 3.50 (dd, J = 14.1, 6.8 Hz, 1H) 3.02 (dd, J = 16.2,5.0 Hz), 1H) 2.89-2.82 (m, 2H) 2.60 (dd, J = 16.2, 8.6 Hz, 1H) 2.49 (s,6H) 2.06-1.95 (m, 1H) 1.77- 1.63 (m, 1H). 344 [M + H]+ 48a

amorphous powder 400 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 2.9, 1.4 Hz,1H) 7.66 (dd, J = 5.0, 2.9 Hz, 1H) 7.28 (dd, J = 5.0, 1.4 Hz, 1H)7.08-7.05 (m, 3H) 7.05- 7.01 (m, 1H) 4.64 (dd, J = 7.5, 6.0 Hz, 1H) 4.00(dd, J = 14.9, 7.5 Hz, 1H) 4.02-3.94 (m, 1H) 3.62 (dd, J = 14.9, 6.0 H,1H) 3.04 (dd, J = 16.2, 5.1 Hz, 1H) 2.90 (s, 3H) 2.91-2.85 (m, 2H) 2.73(s, 3H) 2.64 (dd, J = 16.2, 8.5 Hz, 1H) 2.11-1.96 (m, 1H) 1.80-1.66 (m,1H). 344 [M + H]+ 49a

foam 400 MHz ¹H-NMR (CD₃OD, ppm) 7.76 (dd, J = 2.9, 1.3 Hz, 1H) 7.64(dd, J = 5.1, 2.9 Hz, 1H) 7.28 (dd, J = 5.1, 1.3 Hz, 1H) 6.97-6.91 (m,1H) 6.75 (d, J = 2.4 Hz, 1H) 6.52 (dd, J = 8.3, 2.4 Hz, 1H) 4.71 (dd, J= 8.0, 6.0 Hz, 1H) 4.07 (dd, J = 14.6, 8.0 Hz, 1H) 3.66 (dd, J = 14.6,6.0 Hz, 1H) 3.64-3.57 (m, 2H) 2.81 (s, 6H) 2.63 (t, J = 6.5 Hz, 2H)1.93-1.81 (m, 2H). 346 [M + H]+ 50a

foam 400 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 3.0, 1.3 Hz, 1H) 7.65(dd, J = 5.0, 3.0 Hz, 1H) 7.29 (dd, J = 5.0, 1.3 Hz, 1H) 6.88 (d, J =8.3 Hz, 1H) 6.55 (dd, J = 8.3, 2.6 Hz, 1H) 6.47 (d, J = 2.6 Hz, 1H)4.70-4.60 (m, 1H) 4.08-3.88 (m, 2H) 3.67-3.56 (m, 1H) 2.95 (dd, J =16.1, 4.9 Hz, 1H) 2.89 (s, 3H) 2.80-2.74 (m, 2H) 2.74 (s, 3H) 2.57 (dd,J = 16.1, 8.4 Hz, 1H) 2.07- 1.92 (m, 1H) 1.77-1.60 (m, 1H). 360 [M + H]+51a

amorphous powder 400 MHz ¹H-NMR (CD₃OD, ppm) 7.78-7.73 (m, 1H) 7.65 (dd,J = 5.0, 3.0 Hz, 1H) 7.31-7.25 (m, 1H) 7.11- 6.99 (m, 4H) 4.69-4.59 (m,1H) 4.06- 3.91 (m, 1H) 4.00 (dd, J = 14.9, 7.5 Hz, 1H) 3.62 (dd, J =14.9, 6.0 Hz, 1H) 3.04 (dd, J = 16.2, 5.1 Hz, 1H) 2.96-2.70 (m, 8H) 2.64(dd, J = 16.2, 8.5 Hz, 1H) 2.13-1.95 (m, 1H) 1.80- 1.65 (m, 1H). 344[M + H]+ 52a

amorphous powder 400 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 2.9, 1.4 Hz,1H) 7.66 (dd, J = 5.0, 2.9 Hz, 1H) 7.28 (dd, J = 5.0, 1.4 Hz, 1H)7.11-6.99 (m, 4H) 4.64 (dd, J = 7.5, 6.0 Hz, 1H) 4.00 (dd, J = 14.9, 7.5Hz, 1H) 4.02-3.90 (m, 1H) 3.62 (dd, J = 14.9, 6.0 Hz, 1H) 3.04 (dd, J =16.2, 5.1 Hz, 1H) 2.96- 2.70 (m, 8H) 2.64 (dd, J = 16.2, 8.5 Hz, 1H)2.10-1.98 (m, 1H) 1.80-1.62 (m, 1H). 344 [M + H]+ 53a

163 (dec.) 300 MHz ¹H-NMR (CD₃OD, ppm) 7.76 (dd, J = 3.0, 1.3 Hz, 1H)7.67 (dd, J = 5.1, 3.0 Hz, 1H) 7.28 (dd, J = 5.1, 1.3 Hz, 1H) 6.86 (d, J= 8.6 Hz, 1H) 6.59 (d, J = 2.8 Hz, 1H) 6.54 (dd, J = 8.6, 2.8 Hz, 1H)4.70 (t, J = 7.1 Hz, 1H) 4.06 (dd, J = 14.5, 7.5 Hz, 1H) 3.73-3.44 (m,3H) 2.82 (s, 6H) 2.64 (t, J = 6.7 Hz, 2H) 1.94-1.79 (m, 2H). 346 [M +H]+ 54a

225-227 300 MHz ¹H-NMR (CD₃OD, ppm) 7.32 (s, 4H) 4.75 (s, 4H) 3.70 (s,2H) 2.89 (s, 6H) 2.00-1.89 (m, 2H) 1.88- 1.52 (m, 7H) 1.42-1.24 (m, 1H).302 [M + H]+ 55a

192-194 300 MHz ¹H-NMR (CD₃OD, ppm) 7.15-6.98 (m, 4H) 4.06-3.93 (m, 1H)3.63 (s, 2H) 3.06 (dd, J = 16.3, 5.1 Hz, 1H) 2.93-2.80 (m, 2H) 2.86 (s,6H) 2.66 (dd, J = 16.3, 8.4 Hz, 1H) 2.12- 1.99 (m, 1H) 1.96-1.86 (m, 2H)1.85- 1.44 (m, 8H) 1.41-1.20 (m, 1H). 330 [M + H] 56a

191-193 300 MHz ¹H-NMR (CD₃OD, ppm) 7.11-6.99 (m, 4H) 4.06-3.93 (m, 1H)3.63 (s, 2H) 3.06 (dd, J = 16.2, 5.1 Hz, 1H) 2.93-2.80 (m, 2H) 2.87 (s,6H) 2.67 (dd, J = 16.2, 8.4 Hz, 1H) 2.13- 1.98 (m, 1H) 1.96-1.86 (m, 2H)1.85- 1.44 (m, 8H) 1.40-1.22 (m, 1H). 330 [M + H]+ 57a

amorphous powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.57-7.52 (m, 5H) 7.37-7.25(m, 4H) 4.76-4.62 (m, 4H) 4.58 (dd, J = 8.2, 5.1 Hz, 1H) 4.16 (dd, J =15.1, 8.2 Hz, 1H) 3.72 (dd, J = 15.1, 5.1 Hz, 1H) 2.94 (s, 3H) 2.77 (s,3H). 310 [M + H]+ [α] = −2.4 (0.86, acetone), free amine 58a

amorphous powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.57-7.52 (m, 5H) 7.37-7.25(m, 4H) 4.76-4.62 (m, 4H) 4.57 (dd, J = 8.1, 5.1 Hz, 1H) 4.16 (dd, J =15.0, 8.1 Hz, 1H) 3.71 (dd, J = 15.0, 5.1 Hz, 1H) 3.05-2.62 (m, 6H). 310[M + H]+ [α] = +3.4 (0.86, acetone), free amine 59a

foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.82-7.74 (m, 1H) 7.66 (dd, J = 5.0,2.9 Hz, 1H) 7.30 (dd, J = 5.0, 1.3 Hz, 1H) 6.95 (dd, J = 7.9, 7.9 Hz,1H) 6.73 (d, J = 7.9 Hz, 1H) 6.62 (d, J = 7.9 Hz, 1H) 4.68, (q, J = 6.6Hz, 1H) 4.04 (dd, J = 14.6, 7.5 Hz, 1H) 3.76-3.52 (m, 2H) 2.91 (s, 3H)2.75 (s, 3H) 2.69- 2.50 (m, 2H) 1.96-1.82 (m, 2H) 1.82- 1.71 (m, 2H).360 [M + H]+ 60a

amorphous powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.76 (dd, J = 2.9, 1.3 Hz,1H) 7.65 (dd, J = 5.1, 2.9 Hz, 1H) 7.28 (dd, J = 5.1, 1.3 Hz, 1H) 6.88(d, J = 8.2 Hz, 1H) 6.55 (dd, J = 8.2, 2.6 Hz, 1H) 6.47 (d, J = 2.6 Hz,1H) 4.64 (ddd, J = 8.0, 6.0, 2.3 Hz, 1H) 4.08-3.87 (m, 2H) 3.61 (ddd, J= 14.8, 6.0, 4.0 Hz) 2.95 (dd, J = 16.3, 5.1 Hz, 1H) 2.90-2.65 (m, 8H)2.56 (dd, J = 16.3, 8.4 Hz, 1H) 2.07-1.91 (m, 1H) 1.79-1.61 (m, 1H). 360[M + H]+ 61a

241-243 300 MHz ¹H-NMR (CD₃OD, ppm) 7.33 (dd, J = 8.4, 5.0 Hz, 1H) 7.13-6.99 (m, 2H) 4.77-4.69 (m, 4H) 4.04- 3.94 (m, 2H) 3.84 (s, 2H) 3.76-3.64(m, 2H) 2.93 (s, 6H) 2.07-1.85 (m, 4H). 322 [M + H]+ 62a

200-202 300 MHz ¹H-NMR (CD₃OD, ppm) 7.33 (dd, J = 8.4, 4.9 Hz, 1H) 7.13-6.99 (m, 2H) 4.76-4.69 (m, 4H) 3.53 (s, 2H) 2.89 (s, 6H) 1.39 (s, 6H).280 [M + H]+ 63a

amorphous powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.33 (dd, J = 8.4, 4.9 Hz,1H) 7.12- 7.01 (m, 2H) 4.76-4.65 (m, 4H) 3.59 (s, 2H) 2.95 (s, 6H)2.09-1.74 (m, 8H). 306 [M + H]+ 64a

amorphous powder 300 MHz ¹H-NMR (CD₃OD, ppm) 7.39-7.22 (m, 4H) 4.74 (s,4H) 3.59 (s, 2H) 2.95 (s, 6H) 2.09-1.76 (m, 8H). 288 [M + H]+ 65a

204-206 300 MHz ¹H-NMR (CD₃OD, ppm) 7.12-6.99 (m, 4H) 4.05-3.91 (m, 1H)3.51 (s, 2H) 3.05 (dd, J = 16.2, 5.1 Hz, 1H) 2.95-2.83 (m, 2H) 2.91 (s,6H) 2.66 (dd, J = 16.2, 8.5 Hz, 1H) 2.14- 1.98 (m, 1H) 1.98-1.66 (m,9H). 316 [M + H]+ 66a

164-166 300 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 2.9, 1.1 Hz, 1H) 7.65(dd, J = 5.0, 2.9 Hz, 1H) 7.29 (dd, J = 5.0, 1.1 Hz, 1H) 7.11-6.98 (m,4H) 4.70- 4.60 (m, 1H) 4.08-3.94 (m, 2H) 3.62 (ddd, J = 14.8, 5.8, 3.8Hz, 1H) 3.04 (dd, J = 16.2, 4.9 Hz, 1H) 2.95-2.69 (m, 8H) 2.64 (dd, J =16.2, 8.6 Hz, 1H) 2.10-1.09 (m, 1H) 1.80-1.64 (m, 1H). 344 [M + H]+ 67a

165-167 300 MHz ¹H-NMR (CD₃OD, ppm) 7.80-7.73 (m, 1H) 7.65 (dd, J = 5.0,2.9 Hz, 1H) 7.29 (dd, J = 5.0, 1.1 Hz, 1H) 7.11-6.98 (m, 4H) 4.69-4.59(m, 1H) 4.07-3.90 (m, 2H) 3.62 (ddd, J = 14.8, 5.8, 3.8 Hz, 1H) 3.04(dd, J = 16.3, 5.0 Hz, 1H) 2.91-2.84 (m, 2H) 2.80 (s, 6H) 2.64 (dd, J =16.3, 8.7 Hz, 1H) 2.10-1.97 (m, 1H) 1.80-1.64 (m, 1H). 344 [M + H]+ 68a

145-146 300 MHz ¹H-NMR (CD₃OD, ppm) 7.47-7.39 (m, 2H) 7.12-6.99 (m, 3H)6.89 (dd, J = 9.0, 3.0 Hz, 1H) 6.83- 6.71 (m, 2H) 4.52 (t, J = 7.2, 1H)4.15- 4.04 (m, 1H) 3.86 (s, 3H) 3.76-3.47 (m, 3H) 2.91 (s, 3H) 2.72 (s,3H) 2.80-2.60 (m, 2H) 1.88 (pentet, J = 6.5 Hz, 2H). 372 [M + H]+ 69a

very hygroscopic foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.61-7.46 (m, 5H)7.17-7.09 (m, 1H) 7.07-6.91 (m, 3H) 4.57 (t, J = 7.0, 1H) 4.12 (dd, J =14.4, 7.0 Hz, 1H) 3.74 (dd, J = 14.4, 7.0 Hz, 1H) 3.69-3.44 (m, 2H) 2.86(s, 6H) 2.74-2.59 (m, 2H) 1.88 (pentet, J = 6.5 Hz, 2H). 324 [M + H]+70a

very hygroscopic foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.61-7.46 (m, 5H) 7.00(dd, J = 9.0, 5.1 Hz, 1H) 6.88 (dd, J = 9.0, 3.0 Hz, 1H) 6.78 (ddd, J =9.0, 9.0, 3.0 Hz, 1H) 4.56 (t, J = 7.0, 1H) 4.10 (dd, J = 14.4, 7.0 Hz,1H) 3.73 (dd, J = 14.4, 7.0 Hz, 1H) 3.69-3.48 (m, 2H) 2.85 (s, 6H)2.74-2.62 (m, 2H) 1.88 (pentet, J = 6.4 Hz, 2H). 342 [M + H]+ 71a

112-114 300 MHz ¹H-NMR (CD₃OD, ppm) 7.79-7.74 (m, 1H) 7.64 (dd, J = 5.0,2.9 Hz, 1H) 7.33-7.27 (m, 1H) 7.16- 6.99 (m, 4H) 4.55 (dd, J = 8.9, 6.5Hz, 1H) 4.01-3.86 (m, 1H) 3.37-3.13 (m, 1H) 3.12-2.97 (m, 2H) 2.93-2.82(m, 2H) 2.78 (s, 3H) 2.72 (s, 3H) 2.65 (dd, J = 16.3, 8.9 Hz, 1H)2.45-2.14 (m, 2H) 2.11-1.96 (m, 1H), 1.80-1.62 (m, 1H). 358 [M + H]+ 72a

147-149 300 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 3.0, 1.3 Hz, 1H) 7.63(dd, J = 5.1, 3.0 Hz, 1H) 7.30 (dd, J = 5.1, 1.3 Hz, 1H) 7.11-6.98 (m,4H) 4.55 (dd, J = 9.2, 6.2 Hz, 1H) 4.01-3.86 (m, 1H) 3.37-3.13 (m, 1H)3.12-2.96 (m, 2H) 2.94-2.84 (m, 2H) 2.74 (s, 6H) 2.63 (dd, J = 16.2, 8.7Hz, 1H) 2.45- 2.14 (m, 2H) 2.11-1.96 (m, 1H) 1.81- 1.64 (m, 1H). 358[M + H]+ 73a

147-148 300 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 2.9, 1.4 Hz, 1H) 7.64(dd, J = 5.0, 2.9 Hz, 1H) 7.30 (dd, J = 5.0, 1.4 Hz, 1H) 7.11-7.00 (m,4H) 4.55 (dd, J = 9.1, 6.4 Hz, 1H) 4.01-3.86 (m, 1H) 3.36-3.16 (m, 1H)3.13-2.98 (m, 2H) 2.94-2.84 (m, 2H) 2.78 (s, 3H) 2.73 (s, 3H) 2.63 (dd,J = 16.2, 8.7 Hz, 1H) 2.44-2.17 (m, 2H) 2.11-1.96 (m, 1H) 1.83-1.64 (m,1H). 358 [M + H]+ 74a

144-146 300 MHz ¹H-NMR (CD₃OD, ppm) 7.82-7.74 (m, 1H) 7.67-7.59 (m, 1H)7.31 (d, J = 5.0, 1H) 7.11-7.00 (m, 4H) 4.62-4.49 (m, 1H) 4.01-3.86 (m,1H) 3.36-3.15 (m, 1H) 3.11-2.95 (m, 2H) 2.93-2.82 (m, 2H) 2.78 (s, 3H)2.73 (s, 3H) 2.65 (dd, J = 16.2, 8.8 Hz, 1H) 2.44-2.17 (m, 2H) 2.11-1.96(m, 1H) 1.80-1.64 (m, 1H). 358 [M + H]+ 75a

hygroscopic foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.81-7.73 (m, 1H) 7.63 (dd,J = 5.1, 2.9 Hz, 1H) 7.39-7.18 (m, 6H) 4.58 (dd, J = 9.0, 6.3 Hz, 1H)3.81-3.68 (m, 1H) 3.63-3.49 (m, 1H) 3.49-3.11 (m, 5H) 2.77 (s, 3H) 2.72(s, 3H) 2.46- 2.20 (m, 3H) 2.13-1.96 (m, 1H). 358 [M + H]+ 76a

hygroscopic foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 3.0, 1.3 Hz,1H) 7.64 (dd, J = 5.1, 3.0 Hz, 1H) 7.39-7.18 (m, 6H) 4.58 (dd, J = 9.0,6.3 Hz, 1H) 3.81-3.68 (m, 1H) 3.62-3.51 (m, 1H) 3.49-3.11 (m, 5H) 2.76(s, 3H) 2.73 (s, 3H) 2.47-2.18 (m, 3H) 2.15-1.97 (m, 1H). 358 [M + H]+77a

hygroscopic foam 300 MHz ¹H-NMR (CD₃OD, ppm) 7.77 (dd, J = 3.0, 1.3 Hz,1H) 7.64 (dd, J = 5.1, 3.0 Hz, 1H) 7.35-7.20 (m, 6H) 4.58 (dd, J = 9.0,6.3 Hz, 1H) 3.81- 3.68 (m, 1H) 3.62-3.51 (m, 1H) 3.51- 3.11 (m, 5H) 2.76(s, 3H) 2.73 (s, 3H) 2.45-2.21 (m, 3H) 2.15-1.97 (m, 1H). 358 [M + H]+78a

amorphous powder 300 MHz 1H-NMR (CD₃OD, ppm): 7.69-7.64 (m, 1H) 7.62(dd, J = 5.0, 3.0 Hz, 1 H) 7.36-7.23 (m, 4H) 7.26 (dd, J = 5.0, 1.2 Hz,1H) 4.70 (s, 4 H) 4.53 (dd, J = 7.8, 4.5 Hz, 1H) 3.83 (dd, J = 14.8, 7.8Hz, 1H) 3.66 (dd, J = 14.8, 4.5 Hz, 1H) 2.57 (s, 3 H). 302 [M + H]+ 79a

amorphous powder 300 MHz 1H-NMR (CD₃OD, ppm): 7.67-7.64 (m, 1H) 7.62(dd, J = 5.0, 3.0 Hz, 1H) 7.35-7.29 (m, 4H) 7.26 (dd, J = 5.0, 1.2 Hz,1H) 4.70 (s, 4H) 4.51 (dd, J = 7.8, 4.5 Hz, 1H) 3.82 (dd, J = 14.8, 7.8Hz, 1H) 3.66 (dd, J = 14.8, 4.5 Hz, 1H) 2.57 (s, 3 H). 302 [M + H]+ 80a

amorphous powder 300 MHz 1H-NMR (CD₃OD, ppm): 7.69-7.65 (m, 1H), 7.63(dd, J = 5.0, 3.1 Hz, 1H) 7.40-7.29 (m, 1H) 7.26 (dd, J = 5.0, 1.2 Hz,1H) 7.19-7.11 (m, 1H) 7.08-6.99 (m, 1H) 4.75 (s, 4H) 4.53 (dd, J = 7.8,4.5 Hz, 1H) 3.83 (dd, J = 14.8, 7.8 Hz, 1H) 3.66 (dd, J = 14.8, 4.5 Hz,1H) 2.58 (s, 3H). 320 [M + H]+ 81a

amorphous powder 300 MHz 1H-NMR (CD₃OD, ppm): 7.70-7.65 (m, 1H), 7.63(dd, J = 5.0, 3.0 Hz, 1H) 7.40-7.30 (m, 1H) 7.27 (dd, J = 5.0, 1.2 Hz,1H) 7.19-7.11 (m, 1H) 7.09-6.98 (m, 1H) 4.75 (s, 4H) 4.54 (dd, J = 7.8,4.5 Hz, 1H) 3.83 (dd, J = 14.8, 7.8 Hz, 1H) 3.66 (dd, J = 14.8, 4.5 Hz,1H) 2.58 (s, 3H). 320 [M + H]+ 82a

amorphous powder 300 MHz 1H-NMR (CD₃OD, ppm): 7.34-7.36 (m, 2H) 7.32(dd, J = 8.3, 5.0 Hz, 1H) 7.12-6.99 (m, 4H) 4.77- 4.57 (m, 4H) 4.32 (dd,J = 8.1, 4.6 Hz, 1H) 3.84 (dd, J = 14.8, 8.1 Hz, 1H) 3.82 (s, 3H) 3.61(dd, J = 14.8, 4.6, 1H) 2.55 (s, 3H). 344 [M + H]+ 83a

amorphous powder 300 MHz 1H-NMR (CD₃OD, ppm): 7.50-7.39 (m, 2H) 7.34(dd, J = 8.3, 5.0 Hz, 1H) 7.16-7.01 (m, 4H) 4.79- 4.58 (m, 4H) 4.34 (dd,J = 8.1, 4.6 Hz, 1H) 3.87 (dd, J = 14.8, 8.1 Hz, 1H) 3.85 (s, 3H) 3.64(dd, J = 14.8, 4.6, 1H) 2.55 (s, 3H). 344 [M + H]+

Example 33 Bias Factor of Selected Compounds of the Invention

${\Delta \; {RA}} = {{{LOG}\left( \frac{E\; {MAX}_{\beta - {Arr}}}{{EC}\; 50_{\beta - {Arr}}} \right)} - {{LOG}\left( \frac{E\; {MAX}_{G - {Protein}}}{{EC}\; 50_{G - {Protein}}} \right)}}$Bias Factor (ΔRA of compound relative to ARA CMPD_ID; cAMP cAMPβ-Arrestin β-Arrestin ΔRA of of DAMGO) EX # EC₅₀ (uM) E_(max) (%) EC₅₀(μM) E_(max) (%) compound x10 DAMGO 0.00 108.2 0.06 98.33 −1.48 0.00Morphine 0.06 119.5 0.31 28.80 −1.33 1.51 (1a); 0.020 69.2 0.186 5.67−2.06 −5.75 Ex 3 (2a-ent-(−)); 0.012, 55.5, 30.4 >100 <1 <−2.96 <−14.83Ex 5 0.015 (2a-ent-(+)); 0.018, 99.5, 95.4 1.08, 1.01 6.57, 13.7 −2.40−9.24 Ex 6 0.058 (3a); 0.014 94.2 0.310 21.90 −1.99 −5.07 Ex 7(4a), >100 20.7 >100 <1 NA NA Ex 8 (5a); >100 5.00 >100 <1 NA NA Ex 9(6a); 0.009 21.9 >100 <1 <−2.96 <−14.83 Ex 10 (7a); 0.407 92.1 >100 <1<−2.96 <−14.83 Ex 11 (8a); 0.730 86.9 >100 6.18 <−2.96 <−14.83 Ex 12(9a); 0.512 75.7 4.36 5.11 −2.10 −6.20 Ex 13 (10a); 0.004 85.5 >100 3.33<−2.96 <−14.83 Ex 14 (11a); <0.001 94.3 0.021 111.9 −1.24 2.32 Ex 15(12a); >100 6.33 >100 2.16 NA NA Ex 16 (13a) 0.068 95.3 1.68 11.3 −2.3−8.39 Ex 17 (14a) 0.056 102.0 3.96 61.2 −2.07 −5.91 Ex 18 (15a) 0.015108.5 1.37 44.2 −2.35 −8.71 Ex 19 (16a) 0.026 91.9 0.95 12.2 −2.44 −9.60Ex 20 (17a) 0.043 110.6 5.12 27.0 −2.69 −12.08 Ex 21 (18a) 0.023 100.40.73 6.91 −2.66 −11.84 Ex 22 (19a) 0.032 86.1 >100 2.34 <−2.96 <−14.83Ex 23 (20a) 0.031 70.8 >100 3.65 <−2.96 <−14.83 Ex 24 (68a) 0.167 94.614.589 39.9 −2.32 −8.36 (69a) 0.563 109.6 8.556 8.0 −2.32 −8.38 (70a)0.512 90.3 10.967 5.3 −2.56 −10.82 (30-R) 0.603 109.4 5.729 9.2 −2.05−5.73 Ex 28 (30-S) 0.688 96.1 >100 9.9 <−2.96 <−14.83 Ex 29 (66) 0.00880.5 >100 4.1 <−2.96 <−14.83 (67) 0.013 50.9 >100 2.6 <−2.96 <−14.83(34) >100 2.6 >100 <1 NA NA Ex 30 (35) 1.171 26.4 >100 <1 <−2.96 <−14.83Ex 31 (72) 0.197 111.9 2.611 39.1 −1.58 −0.99 (71) 0.177 71.2 1.823 10.5−1.85 −3.66 (39) 0.118 93.4 0.644 10.9 −1.67 −1.90 (40) 0.152 53.5 >1003.3 <−2.96 <−14.83 (73) 0.422 13.6 >100 <1 <−2.96 <−14.83 (42) 7.42921.9 >100 <1 <−2.96 <−14.83 (43) 1.716 54.2 >100 <1 <−2.96 <−14.83(41) >100 9.6 >100 <1 NA NA (74) >100 11.2 >100 <1 NA NA (44) 0.16251.4 >100 5.3 <−2.96 <−14.83 (45) 0.276 101.4 >100 8.1 <−2.96 <−14.83(75) 2.088 113.5 16.956 12.2 −1.88 −3.97 (76) 1.761 33.0 >100 <1 <−2.96<−14.83 (21) >100 4.5 >100 <1 NA NA Ex 25 (77) 1.097 33.2 >100 <1 <−2.96<−14.83 (46) 0.522 108.7 10.075 13.6 −2.19 −7.08 (47) 0.010 93.0 >100 <1<−2.96 <−14.83 (48) 0.260 31.8 >100 <1 <−2.96 <−14.83 (22) 0.32216.3 >100 <1 <−2.96 <−14.83 Ex 26 (24) >100 <10 >100 <1 <−2.96 <−14.83Ex 27 (49) 0.998 97.0 >100 <1 <−2.96 <−14.83 (50) 0.036 48.3 >100 <1<−2.96 <−14.83 (51) 0.029 64.9 >100 <1 <−2.96 <−14.83 (52) 0.22712.2 >100 <1 <−2.96 <−14.83 (53) 0.267 119.7 3.790 20.1 −1.93 −4.47 (54)0.396 113.4 4.424 20.8 −1.78 −3.04 (55) 2.853 36.6 >100 <1 <−2.96<−14.83 (56) 7.737 43.3 >100 <1 <−2.96 <−14.83 (57) 0.072 89.4 >100 <1<−2.96 <−14.83 (58) 0.132 109.1 1.887 35.2 −1.65 −1.66 (59) 0.006 108.20.160 61.0 −1.67 −1.95 (60) 0.676 27.5 >100 <1 <−2.96 <−14.83 (61) 1.174103.9 >100 14.5 <−2.96 <−14.83 (62) 21.009 81.8 >100 <1 <−2.96 <−14.83(63) 2.511 87.9 >100 <1 <−2.96 <−14.83 (64) 2.151 88.7 >100 <1 <−2.96<−14.83 (65) >100 <10 >100 <1 NA NA (38) 0.045 95.9 1.674 6.6 −2.74−12.56 Ex 32 (38-ent-A) 0.379 81.6 >100 3.7 <−2.96 <−14.83 Ex 32(38-ent-B) 0.840 97.6 >100 5.9 <−2.96 <−14.83 Ex 32 (78) 0.362104.0 >100 12.8 <−2.96 <−14.83 (79) 0.087 64.2 >100 1.7 <−2.96 <−14.83(80) 0.041 102.9 1.396 25.2 −2.14 −6.64 (81) 0.014 91.6 >100 8.2 <−2.96<−14.83 (82) 0.457 83.2 >100 2.7 <−2.96 <−14.83 (83) 0.057 100.1 >10013.4 <−2.96 <−14.83

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1. A compound of formula (I), or a salt, solvate, enantiomer,diastereoisomer or tautomer thereof:

wherein: A is selected from the group consisting of

B¹ is selected from the group consisting of

and B² is H; or B¹ and B² are independently selected from the groupconsisting of —CH₃ and —CH₂CH₃, or B¹ and B² combine to form a divalentsubstituent selected from the group consisting of —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, and —CH₂CH₂OCH₂CH₂—; R¹ and R² are independentlyselected from the group consisting of H, CH₃, and CH₃ substituted withat least one selected from the group consisting of fluoro, chloro,cyano, hydroxyl and nitro; R³ is selected from the group consisting of Hand CH₃, X is selected from the group consisting of S, O, and N—R³; eachoccurrence of R is independently selected from the group consisting offluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,phenyl, and substituted phenyl; each occurrence of m is independentlyselected from the group consisting of 0, 1, 2 and 3; n is selected fromthe group consisting of 1, 2 and 3; and each occurrence of p isindependently selected from the group consisting of 0, 1, 2 and
 3. 2-3.(canceled)
 4. The compound of claim 1, wherein A is


5. The compound of claim 1, wherein A is


6. (canceled)
 7. The compound of claim 1, wherein B¹ is


8. The compound of claim 1, wherein B¹ is


9. The compound of claim 1, wherein B¹ is


10. The compound of claim 1, wherein A is selected from the groupconsisting of 1,2,3,4-tetrahydronaphthalen-1-yl,1,2,3,4-tetrahydronaphthalen-2-yl,5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl,6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl,7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl,8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl,5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl,6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl,7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl,8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl,5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl,6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl,7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl,8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl,5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl,6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl,7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, and8-hydroxy-1,2,3,4-tetrahydronaphthalen 2 yl.
 11. The compound of claim1, wherein B² is H, and wherein B¹ is selected from the group consistingof 3-thienyl, 2-thienyl, 2-chloro-4-fluorophenyl,4-chloro-2-fluorophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, and phenyl.12. The compound of claim 1, wherein B¹ is CH₃ and B² is CH₃.
 13. Acompound, or a salt, solvate, enantiomer, diastereoisomer or tautomerthereof, selected from the group consisting of:N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;(−)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;(+)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamide;5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide;1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamide;3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)- 1-methyl- 1-(1,2,3,4-tetrahydronaphthal en- 1-yl)urea; 1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3 ,4-tetrahydronaphthalen-2-yl)urea;3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;(R)-3-Phenyl-pyrrolidine-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;(S)-3-Phenyl-pyrrolidine-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;4-Cyano-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclohexylmethyl)-amide hydrochloride;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea-;7-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((R)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;1,3-Dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclohexylmethyl)-amide;(R)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;(S)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((S)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(4-dimethylamino-tetrahydro-pyran-4-ylmethyl)-amide;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-methyl-propyl)-amide;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclopentylmethyl)-amide;1,3-Dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclopentylmethyl)-amide;1-(1-Dimethylamino-cyclopentylmethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;(R)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(S)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(S)—N—((S)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(−)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(+)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(−)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(+)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;(S)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-hydroxyisoindoline-2-carboxamide;and5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide14. A pharmaceutical composition comprising at least onepharmaceutically acceptable carrier and at least one compound ofclaim
 1. 15. A method of treating or ameliorating pain in a subject, themethod comprising administering to the subject a therapeuticallyeffective amount of at least one compound of claim
 1. 16. The method ofclaim 15, wherein the at least one compound is selected from the groupof:N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;(−)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;(+)-ent-N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-4-fluoroisoindoline-2-carboxamide;5-Chloro-N-(2-(dimethylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methoxyisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5,6-difluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-6-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide;1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-methylisoindoline-2-carboxamide;3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;(R)-3-Phenyl-pyrrolidine-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;(S)-3-Phenyl-pyrrolidine-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;4-Cyano-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclohexylmethyl)-amide hydrochloride;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;7-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((R)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid(2-dimethylamino-2-thiophen-3-yl-ethyl)-amide;1,3-Dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclohexylmethyl)-amide;(R)-1-((1-(Dimethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;(S)-1-((1-(Dim ethylamino)cyclohexyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((S)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(4-dimethylamino-tetrahydro-pyran-4-ylmethyl)-amide;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(2-dimethylamino-2-methyl-propyl)-amide;5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclopentylmethyl)-amide;1,3-Dihydro-isoindole-2-carboxylic acid(1-dimethylamino-cyclopentylmethyl)-amide;1-(1-Dimethylamino-cyclopentylmethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;(R)—N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(S)-N—((R)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(S)-N—((S)-3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-3-phenylpyrrolidine-1-carboxamide;(−)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(+)-N-(2-(Methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(−)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(+)-4-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide;(R)—N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;(S)-N-(3-(Dimethylamino)-3-(thiophen-3-yl)propyl)-5-fluoroisoindoline-2-carboxamide;N-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-5-hydroxyisoindoline-2-carboxamide;and5-Fluoro-N-(2-(methylamino)-2-(thiophen-3-yl)ethyl)isoindoline-2-carboxamide17. The method of claim 15, wherein the at least one compound is a MORagonist.
 18. The method of claim 15, wherein the at least one compounddecreases cyclic adenosine monophosphate (cAMP) levels in the subject.19. The method of claim 15, wherein the at least one compound does notsignificantly induce recruitment, binding to, or association with aβ-arrestin.
 20. The method of claim 15, wherein the at least onecompound does not significantly cause at least one side effect selectedfrom the group consisting of tachyphylaxis, respiratory depression,constipation, nausea, emesis, withdrawal, dependence, and addiction. 21.The method of claim 15, wherein the pain comprises at least one paintype selected from the group consisting of chronic pain, neuropathicpain, nociceptive pain, hyperalgesia, and allodynia.